Preliminary studies suggest that administration of fish oil fatty acids may be beneficial in several immunological diseases; therefore, we studied the effect of fish oil dietary supplementation on the expression of Ia in stimulated murine peritoneal macrophages. Rats (n = 19) and mice (n = 27) on standard rodent feeding were separated in experimental (E) and control (C) groups that received fish oil or saline solution, respectively, daily for 4 weeks by esophageal gavage. Cholesterol serum levels were significantly lowered by fish oil (E vs C, P < 0.01). E and C groups were injected intraperitoneally with Listeria monocytogenes (LM) and peritoneal cells were harvested 4 and 7 days after infection. Decreased expression of Ia induced by LM was found in rats (C = 49.68 ± 5.09%, E = 16.95 ± 4.3%, P < 0.01) and mice (C = 47.38 ± 7.63%, E = 26.66 ± 1.92%, P < 0.01). Animals with a more pronounced depression of serum cholesterol (reduction of 44.04 ± 1.52% of baseline levels) had more depression of Ia expression (6.47 ± 1.22%, P < 0.001 vs control). Reduction of Ia expression was not related to PGE2 production by peritoneal cells. Reduction of Ia expression by fish oil could induce down-regulation of antigen presentation and alloreactivity.