OBJECTIVE: High consumption of ω-3 polyunsaturated fatty acids (PUFAs) has been associated with lower plasma homocystine (Hcy) levels, but intervention studies in humans have been inconclusive. The objective was to systematically evaluate the effects of ω-3 PUFA supplementation on plasma Hcy levels. METHODS: A comprehensive search of Medline, EMBASE, the Cochrane Clinical Trials Registry, and bibliographies of relevant articles published from 1966 through September 2010 was undertaken. All randomized, placebo-controlled trials that compared ω-3 PUFA supplementation with placebo were included. Two investigators performed data extraction and quality scoring independently, with discrepancies resolved by consensus. RESULTS: Eleven trials including 702 subjects were analyzed. The outcomes studied were plasma Hcy level. Eleven randomized, placebo-controlled trials were included in this meta-analysis. Supplementation with ω-3 PUFAs was associated with a significant decrease in plasma Hcy level (weighted mean difference -1.59 μmol/L, 95% confidence interval -2.34 to -0.83) compared with control subjects. CONCLUSION: This meta-analysis suggested that ω-3 PUFA supplementation can decrease plasma Hcy levels. The implications of these findings remain to be elucidated.