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Background: Preclinical data have shown that low levels of metabolites with anti-inflammatory properties may impact metabolic disease processes. However, the association between mid-life levels of such metabolites and long-term ASCVD risk is not known., Methods: We characterised the plasma metabolomic profile (1228 metabolites) of 1852 participants (58.1 ± 7.5 years old, 69.6% female, 43.6% self-identified as Black) enrolled in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study. Logistic regression was used to assess the impact of metabolite levels on ASCVD risk (nonfatal MI, revascularisation, and cardiac mortality). We additionally explored the effect of genetic variants neighbouring ASCVD-related genes on the levels of metabolites predictive of ASCVD events. The Atherosclerosis Risk in Communities (ARIC) study (n = 4790; 75.5 ± 5.1 years old, 57.4% female, 19.5% self-identified as Black) was used as an independent validation cohort., Findings: In fully adjusted models, alpha-ketobutyrate [AKB] (OR 0.62 [95% CI, 0.49-0.80]; p < 0.001), and 1-palmitoyl-2-linoleoyl-GPI [OR, 0.62, 95% CI, 0.47-0.83; p < 0.001], two metabolites in amino acid and phosphatidylinositol lipid pathways, respectively, showed a significant protective association with incident ASCVD risk in both Heart SCORE and ARIC cohorts. Three plasmalogens and a bilirubin derivative, whose levels were regulated by genetic variants neighbouring FADS1 and UGT1A1, respectively, exhibited a significant protective association with ASCVD risk in the Heart SCORE only., Interpretation: Higher mid-life levels of AKB and 1-palmitoyl-2-linoleoyl-GPI metabolites may be associated with lower risk late-life ASCVD events. Further research can determine the causality and therapeutic potential of these metabolites in ASCVD., Funding: This study was funded by the Pennsylvania Department of Health (ME-02-384). The department specifically disclaims responsibility for any analyses, interpretations, or conclusions. Additional funding was provided by National Institutes of Health (NIH) grant R01HL089292 and UL1 TR001857 (Steven Reis). Further, NIH funded R01HL141824 and R01HL168683 were used for the ARIC study validation (Bing Yu)., Competing Interests: Declaration of interests The authors report no conflicts of interest relevant to this work. Anum Saeed is supported by 23CDA1055489 by the American Heart Association. Steven Reis has received funding for this study by the Department of Health of Commonwealth of Pennsylvania and National Institute of Health (NIH). Mark Mapstone is supported by U19 AG078109, U19 AG068054, R01 AG058644 and R01AG056726 by the National Aging Institute (NIA) and National Institute for Child Health and Development and reports royalty payments by the University of Rochester and consulting fees from NovoGlia and Ireneo Health. Ann D. Cohen is supported by the NIH/NIA and reports travel support by Biogen, spouse is a Quest employee, and honoraria received from UT Austin. Oscar L. Lopez receives consulting fees from Novo Nordisk which is not relevant to this work. Chris McKennan receives consulting fees from Signature Dx (unrelated to this manuscript) and grant funding from the NIH NIA and NIAID and reports participation in DUSK trial, RIGHT Study, and DEEP trial. The remaining authors have no disclosures relevant to this manuscript., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)