Background: The plant-based Portfolio dietary pattern includes recognized cholesterol-lowering foods (ie, plant protein, nuts, viscous fiber, phytosterols, and plant monounsaturated fats) shown to improve several cardiovascular disease (CVD) risk factors in randomized controlled trials. However, there is limited evidence on the role of long-term adherence to the diet and CVD risk. The primary objective was to examine the relationship between the Portfolio Diet Score (PDS) and the risk of total CVD, coronary heart disease (CHD), and stroke., Methods: We prospectively followed 73 924 women in the Nurses' Health Study (1984-2016), 92 346 women in the Nurses' Health Study II (1991-2017), and 43 970 men in the Health Professionals Follow-up Study (1986-2016) without CVD or cancer at baseline. Diet was assessed using validated food frequency questionnaires at baseline and every 4 years using a PDS that positively ranks plant protein (legumes), nuts and seeds, viscous fiber sources, phytosterols (mg/day), and plant monounsaturated fat sources, and negatively ranks foods high in saturated fat and cholesterol., Results: During up to 30 years of follow-up, 16 917 incident CVD cases, including 10 666 CHD cases and 6473 strokes, were documented. After multivariable adjustment for lifestyle factors and a modified Alternate Healthy Eating Index (excluding overlapping components), comparing the highest with the lowest quintile, participants with a higher PDS had a lower risk of total CVD (pooled hazard ratio [HR], 0.86 [95% CI, 0.81-0.92]; P trend <0.001), CHD (pooled HR, 0.86 [95% CI, 0.80-0.93]; P trend =0.0001), and stroke (pooled HR, 0.86 [95% CI, 0.78-0.95]; P trend =0.0003). In addition, a 25-percentile higher PDS was associated with a lower risk of total CVD (pooled HR, 0.92 [95% CI, 0.89-0.95]), CHD (pooled HR, 0.92 [95% CI, 0.88-0.95]), and stroke (pooled HR, 0.92 [95% CI, 0.87-0.96]). Results remained consistent across sensitivity and most subgroup analyses, and there was no evidence of departure from linearity for CVD, CHD, or stroke. In a subset of participants, a higher PDS was associated with a more favorable blood lipid and inflammatory profile., Conclusions: The PDS was associated with a lower risk of CVD, including CHD and stroke, and a more favorable blood lipid and inflammatory profile, in 3 large prospective cohorts., Competing Interests: Disclosures Dr Glenn has received honoraria or travel support from the Soy Nutrition Institute Global, Vinasoy, and the Academy of Nutrition and Dietetics. Dr Malik has received funding from the Canada Research Chairs Program; Connaught New Researcher Award, the Joannah & Brian Lawson Centre for Child Nutrition, and a Temerty Faculty of Medicine Pathway grant, University of Toronto; Canada Foundation for Innovation; and Ontario Research Fund; and is an advisory board member of the Canadian Institutes of Health Research Institute of Nutrition, Metabolism and Diabetes. Dr Jenkins has received research grants from Saskatchewan & Alberta Pulse Growers Associations; the Agricultural Bioproducts Innovation Program through the Pulse Research Network; the Advanced Foods and Material Network; Loblaw Companies Ltd; Unilever Canada and Netherlands; Barilla; the Almond Board of California; Agriculture and Agri-Food Canada; Pulse Canada; Kellogg’s Company Canada; Quaker Oats Canada; Procter & Gamble Technical Centre Ltd; Bayer Consumer Care, Springfield, NJ; Pepsi/Quaker; International Nut & Dried Fruit Council; Soy Foods Association of North America; the Coca-Cola Company (investigator initiated, unrestricted grant); Solae; Haine Celestial; the Sanitarium Company; Orafti; the International Tree Nut Council Nutrition Research and Education Foundation; the Peanut Institute; Soy Nutrition Institute; the Canola and Flax Councils of Canada; the Calorie Control Council; the Canadian Institutes of Health Research; the Canada Foundation for Innovation; and the Ontario Research Fund; has received in-kind supplies for trials as research support from the Almond Board of California, Walnut Council of California, the Peanut Institute, Barilla, Unilever, Unico, Primo, Loblaw Companies, Quaker (PepsiCo), Pristine Gourmet, Bunge Limited, Kellogg Canada, and WhiteWave Foods; has been on the speaker’s panel, served on the scientific advisory board, or received travel support or honoraria from Nutritional Fundamentals for Health–Nutramedica, Saint Barnabas Medical Center, The University of Chicago, 2020 China Glycemic Index International Conference, Atlantic Pain Conference, Academy of Life Long Learning, the Almond Board of California, Canadian Agriculture Policy Institute, Loblaw Companies Ltd, the Griffin Hospital (for the development of the NuVal scoring system), the Coca-Cola Company, Epicure, Danone, Diet Quality Photo Navigation, Better Therapeutics (FareWell), Verywell, True Health Initiative, Heali AI Corp, Institute of Food Technologists, Soy Nutrition Institute, Herbalife Nutrition Institute, Saskatchewan & Alberta Pulse Growers Associations, Sanitarium Company, Orafti, the International Tree Nut Council Nutrition Research and Education Foundation, the Peanut Institute, Herbalife International, Pacific Health Laboratories, Barilla, Metagenics, Bayer Consumer Care, Unilever Canada and Netherlands, Solae, Kellogg, Quaker Oats, Procter & Gamble, Abbott Laboratories, Dean Foods, the California Strawberry Commission, Haine Celestial, PepsiCo, the Alpro Foundation, Pioneer Hi-Bred International, DuPont Nutrition and Health, Spherix Consulting and WhiteWave Foods, the Advanced Foods and Material Network, the Canola and Flax Councils of Canada, Agri-Culture and Agri-Food Canada, the Canadian Agri-Food Policy Institute, Pulse Canada, the Soy Foods Association of North America, the Nutrition Foundation of Italy, Nutra-Source Diagnostics, the McDougall Program, the Toronto Knowledge Translation Group (St Michael’s Hospital), the Canadian College of Naturopathic Medicine, the Hospital for Sick Children, the Canadian Nutrition Society, the American Society of Nutrition, Arizona State University, Paolo Sorbini Foundation, and the Institute of Nutrition, Metabolism and Diabetes; received an honorarium from the US Department of Agriculture to present the 2013 W.O. Atwater Memorial Lecture; received the 2013 Award for Excellence in Research from the International Nut and Dried Fruit Council; received funding and travel support from the Canadian Society of Endocrinology and Metabolism to produce mini-cases for the Canadian Diabetes Association; and is a member of the International Carbohydrate Quality Consortium; his wife, Alexandra L. Jenkins, is a director and partner of INQUIS Clinical Research for the food industry; his daughters, Wendy Jenkins and Amy Jenkins, have published a book that promotes the use of the foods described here (The Portfolio Diet for Cardiovascular Risk Reduction); and his sister, Caroline Brydson, received funding through a grant from the St Michael’s Hospital Foundation to develop a cookbook for one of his studies. Dr Kendall has received grants or research support from the Advanced Food Materials Network, Agriculture and Agri-Food Canada, Almond Board of California, Barilla, Canadian Institutes of Health Research, Canola Council of Canada, International Nut and Dried Fruit Council, International Tree Nut Council Research and Education Foundation, Loblaw Brands Ltd, the Peanut Institute, Pulse Canada, and Unilever; has received in-kind research support from the Almond Board of California, Barilla, California Walnut Commission, Kellogg Canada, Loblaw Companies, Nutrartis, Quaker (PepsiCo), the Peanut Institute, Primo, Unico, Unilever, and WhiteWave Foods/Danone; has received travel support or honoraria from the Barilla, California Walnut Commission, Canola Council of Canada, General Mills, International Nut and Dried Fruit Council, International Pasta Organization, Lantmannen, Loblaw Brands Ltd, Nutrition Foundation of Italy, Oldways Preservation Trust, Paramount Farms, the Peanut Institute, Pulse Canada, Sun-Maid, Tate & Lyle, Unilever, and White Wave Foods/Danone; has served on the scientific advisory board for the International Tree Nut Council, International Pasta Organization, McCormick Science Institute, and Oldways Preservation Trust; is a founding member of the International Carbohydrate Quality Consortium; is chair of the Diabetes and Nutrition Study Group of the European Association for the Study of Diabetes; is on the clinical practice guidelines expert committee for nutrition therapy of the European Association for the Study of Diabetes; and is a director of glycemia consulting and the Toronto 3D Knowledge Synthesis and Clinical Trials Foundation. Dr Sievenpiper has received research support from the Canadian Foundation for Innovation, Ontario Research Fund, Province of Ontario Ministry of Research and Innovation and Science, Canadian Institutes of health Research (CIHR), Diabetes Canada, American Society for Nutrition (ASN), International Nut and Dried Fruit Council (INC) Foundation, National Honey Board (U.S. Department of Agriculture [USDA] honey “Checkoff” program), Institute for the Advancement of Food and Nutrition Sciences (IAFNS), Pulse Canada, Quaker Oats Center of Excellence, The United Soybean Board (USDA soy “Checkoff” program), The Tate and Lyle Nutritional Research Fund at the University of Toronto, The Glycemic Control and Cardiovascular Disease in Type 2 Diabetes Fund at the University of Toronto (a fund established by the Alberta Pulse Growers), The Plant Protein Fund at the University of Toronto (a fund which has received contributions from IFF), and The Nutrition Trialists Network Research Fund at the University of Toronto (a fund established by an inaugural donation from the Calorie Control Council). He has received food donations to support randomized controlled trials from the Almond Board of California, California Walnut Commission, Peanut Institute, Barilla, Unilever/Upfield, Unico/Primo, Loblaw Companies, Quaker, Kellogg Canada, Danone, Nutrartis, Soylent, and Dairy Farmers of Canada. He has received travel support, speaker fees and/or honoraria from ASN, Danone, Dairy Farmers of Canada, FoodMinds LLC, Nestlé, Abbott, General Mills, Nutrition Communications, International Food Information Council (IFIC), Calorie Control Council, International Sweeteners Association, International Glutamate Technical Committee, Arab Beverages Association, and Phynova. He has or has had ad hoc consulting arrangements with Perkins Coie LLP, Tate & Lyle, Inquis Clinical Research, and Brightseed. He is a former member of the European Fruit Juice Association Scientific Expert Panel and former member of the Soy Nutrition Institute (SNI) Scientific Advisory Committee. He is on the Clinical Practice Guidelines Expert Committees of Diabetes Canada, European Association for the study of Diabetes (EASD), Canadian Cardiovascular Society (CCS), and Obesity Canada/Canadian Association of Bariatric Physicians and Surgeons. He serves as an unpaid member of the Board of Trustees of IAFNS and formerly served as an unpaid scientific advisor for the Carbohydrates Committee of IAFNS. He is a Director at Large of the Canadian Nutrition Society (CNS), founding member of the International Carbohydrate Quality Consortium (ICQC), Executive Board Member of the Diabetes and Nutrition Study Group (DNSG) of the EASD, and Director of the Toronto 3D Knowledge Synthesis and Clinical Trials foundation. His spouse is an employee of AB InBev. The other authors have no conflicts of interests to report.