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Background: Growing evidence indicates that trimethylamine N -oxide, a gut microbial metabolite of dietary choline and carnitine, promotes both cardiovascular disease and chronic kidney disease risk. It remains unclear how circulating concentrations of trimethylamine N -oxide and its related dietary and gut microbe-derived metabolites (choline, betaine, carnitine, γ-butyrobetaine, and crotonobetaine) affect incident heart failure (HF)., Methods: We evaluated 11 768 participants from the Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis with serial measures of metabolites. Cox proportional hazard models were used to examine the associations between metabolites and incident HF, adjusted for cardiovascular disease risk factors., Results: In all, 2102 cases of HF occurred over a median follow-up of 15.9 years. After adjusting for traditional risk factors, higher concentrations of trimethylamine N -oxide (hazard ratio, 1.15 [95% CI, 1.09-1.20]; P <0.001), choline (hazard ratio, 1.44 [95% CI, 1.26-1.64]; P <0.001), and crotonobetaine (hazard ratio, 1.24 [95% CI, 1.16-1.32]; P <0.001) were associated with increased risk for incident HF. After further adjustment for renal function (potential confounder or mediator), these associations did not reach Bonferroni-corrected statistical significance ( P =0.01, 0.049, and 0.006, respectively). Betaine and carnitine were nominally associated with a higher incidence of HF ( P <0.05). In exploratory analyses, results were similar for subtypes of HF based on left ventricular ejection fraction, and associations appeared generally stronger among Black and Hispanic/Latino versus White adults, although there were no interactions for any metabolites with race., Conclusions: In this pooled analysis of 2 well-phenotyped, diverse, community-based cohorts, circulating concentrations of gut microbe-derived metabolites such as trimethylamine N -oxide, choline, and crotonobetaine were independently associated with a higher risk of developing HF., Registration: URL: https://www.clinicaltrials.gov/; Unique identifiers: NCT00005133 and NCT00005487., Competing Interests: Dr Tang is a consultant for Sequana Medical, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics, WhiteSwell, Boston Scientific, CardiaTec Biosciences, Intellia Therapeutics, Bristol Myers Squibb, Alleviant Medical, Alexion Pharmaceuticals, BioCardia, and Salubris Biotherapeutics and has received honorarium from Springer Nature, Belvoir Media Group, and American Board of Internal Medicine. Drs Hazen and Z. Wang report being named as co-inventors on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. Drs Hazen and Z. Wang report having received royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland Heart Lab, a fully owned subsidiary of Quest Diagnostics, and Procter & Gamble. Dr Hazen is a paid consultant for Zehna Therapeutics and Proctor & Gamble and has received research funds from Zehna Therapeutics, Proctor & Gamble, Pfizer Inc, and Roche Diagnostics. Dr Bäckhed reports receiving research support from Biogaia AB, is founder and shareholder of Implexion Pharma AB and Roxbiosens Inc, and is on the scientific advisory board for Bactolife A/S. Dr Psaty reported serving on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Dr Mozaffarian reported receiving personal fees from Acasti Pharma Inc, America’s Test Kitchen, Barilla, Cleveland Clinic Foundation, Danone SA, GOED (Global Organization for EPA and DHA Omega-3s), and Motif FoodWorks; serving on the scientific advisory board for Beren Therapeutics GmbH, Brightseed, Calibrate, DayTwo (ended June 2020), Elysium Health, Filtricine Inc, Foodome, HumanCo, January Inc, Perfect Day Inc, Season, and Tiny Organics; and receiving chapter royalties from UpToDate outside the submitted work. The other authors report no conflicts.