Background: prostaglandin E2 (PGE2) inhibits lymphocyte proliferation and the production of interferon-{gamma} (IFN-{gamma}) by peripheral blood mononuclear cells, but the effect of PGE2 on interleukin 4 (IL-4) production is unclear. Fish oil, which contains eicosapentaenoic and docosahexaenoic acids, inhibits production of PGE2. The effects of fish oil on lymphocyte proliferation and production of IFN-{gamma} and IL-4 are unclear and may be influenced by the availability of antioxidants. Objective: we investigated the effect of dietary fish oil with and without antioxidant cosupplementation on lymphocyte proliferation and the production of PGE2, IFN-{gamma}, and IL-4 by peripheral blood mononuclear cells. Design: sixteen healthy men received dietary fish-oil supplements providing 0.3, 1, and 2 g eicosapentaenoic acid plus docosahexaenoic acid/d for 4 consecutive weeks each (total of 12 wk). All subjects were randomly assigned to daily cosupplementation with either antioxidants (200 µg Se, 3 mg Mn, 30 mg RRR-{alpha}-tocopheryl succinate, 90 mg ascorbic acid, 450 µg vitamin A) or placebo. Results: fish-oil supplementation decreased PGE2 production and increased IFN-{gamma} production and lymphocyte proliferation from baseline values. Cosupplementation with antioxidants did not affect cytokine production or lymphocyte proliferation. Conclusion: dietary fish oil modulates production of IFN-{gamma} and lymphocyte proliferation in a manner consistent with decreased production of PGE2, but this effect is not modified by antioxidant cosupplementation.