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Background: Although a large body of literature reported the beneficial effects of omega-3 fatty acids (omega-3 FAs) consumption on adipokines levels, but recent findings from clinical trials are not univocal. The aim of this systematic review and meta-analysis was to evaluate the effect of omega-3 FAs supplements on adipokines., Methods: We searched Medline, Web of Science, Scopus, Embase, and Cochrane Library from inception to August 2020 without any particular language limitations. Outcomes were summarized as standardized mean difference (SMD) with 95% confidence intervals (CIs) estimated from Hedge's g and random effects modeling., Results: Fifty-two trials involving 4,568 participants were included. Omega-3 FAs intake was associated with a significant increase in plasma adiponectin levels ( n  = 43; 3,434 participants; SMD: 0.21, 95% CI: 0.04, 0.37; p  = 0.01; I 2 = 80.14%). This meta-analysis indicates that supplementing participants with omega-3 fatty acids more than 2000 mg daily and more than 10 weeks resulted in a significant and more favorable improvement in plasma adiponectin levels. However, omega-3 FAs intake had no significant effect on leptin levels (SMD: -0.02, 95% CI: -0.20, 0.17, I 2 = 54.13%)., Conclusion: The evidence supports a beneficial effect of omega-3 FAs intake on serum adiponectin levels but does not appear to impact on leptin concentrations. Larger well-designed RCTs are still required to evaluate the effect of omega-3 FAs on leptin in specific diseases.