Background: Despite growing attention to nutrition and quality of life in cardiovascular disease survivors, the impact of dietary factors according to disease type or to quality of life domain is poorly understood. We investigated the effects of B vitamin and/or n-3 fatty acid supplementation on health-related quality of life among survivors of stroke, myocardial infarction, or unstable angina. Methods: We performed ancillary analyses of the SU.FOL.OM3 trial (2003–2009; France). In total, 2,501 men (mean age = 61 y) and women (mean age = 63 y) were randomized in a 2×2 factorial design to: 1) 0.56 mg 5-methyl-tetrahydrofolate, 3 mg vitamin B6, 0.02 mg vitamin B12; 2) 600 mg eicosapentaenoic and docosahexaenoic acids in a 2∶1 ratio; 3) B vitamins and n-3 fatty acids combined; or 4) placebo. Health-related quality of life was evaluated at follow-up with the Medical Outcomes Study 36-Item Short Form Health Survey. Data from 2,029 individuals were used in this analysis. Results: After 3.1±0.4 y, no effects of supplementation with either B vitamins or n-3 fatty acids on quality of life (physical or mental health domains) were found. However, participants receiving B vitamins had slightly more activity limitations due to emotional problems compared with those not receiving B vitamins (mean difference = 3.8; 95% CI: 0.4, 7.1). A significant interaction of treatment by prior disease revealed an inverse association between n-3 fatty acids and vitality among myocardial infarction survivors (mean difference = 2.9; 95% CI: 0.5, 5.2). Conclusions: There were no beneficial effects of supplementation with relatively low doses of B vitamins or n-3 fatty acids on health-related quality of life in cardiovascular disease survivors. The adverse effects of B vitamins on activity limitations and of n-3 fatty acids on vitality among individuals with prior myocardial infarction merit confirmation.