Background-Early trials evaluating the effect of omega 3 fatty acids (?-3 FA) reported benefits for mortality and cardiovascular events but recent larger studies trials have variable findings. We assessed the effects of ?-3 FA on cardiovascular and other important clinical outcomes. Methods and Results-We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for all randomized studies using dietary supplements, dietary interventions, or both. The primary outcome was a composite of cardiovascular events (mostly myocardial infarction, stroke, and cardiovascular death). Secondary outcomes were arrhythmia, cerebrovascular events, hemorrhagic stroke, ischemic stroke, coronary revascularization, heart failure, total mortality, nonvascular mortality, and end-stage kidney disease. Twenty studies including 63 030 participants were included. There was no overall effect of ?-3 FA on composite cardiovascular events (relative risk [RR]=0.96; 95% confidence interval [CI], 0.90-1.03; P=0.24) or on total mortality (RR=0.95; 95% CI, 0.86-1.04; P=0.28). ?-3 FA did protect against vascular death (RR=0.86; 95% CI, 0.75-0.99; P=0.03) but not coronary events (RR=0.86; 95% CI, 0.67-1.11; P=0.24). There was no effect on arrhythmia (RR=0.99; 95% CI, 0.85-1.16; P=0.92) or cerebrovascular events (RR=1.03; 95% CI, 0.92-1.16; P=0.59). Adverse events were more common in the treatment group than the placebo group (RR=1.18, 95% CI, 1.02-1.37; P=0.03), predominantly because of an excess of gastrointestinal side effects. Conclusions-?-3 FA may protect against vascular disease, but the evidence is not clear-cut, and any benefits are almost certainly not as great as previously believed.