Dietary phytosterols significantly reduce atherosclerosis in apo E-deficient mice. Because atherosclerosis is a chronic inflammatory disease, we investigated whether the antiatherogenic effects of phytosterols are associated with reductions in proinflammatory cytokine production as well as the effect of this diet on global immunocompetence. Apolipoprotein (apo) E-deficient mice were fed a cholesterol-supplemented diet in the presence or absence of 2% dietary phytosterols for 14 wk and then immunized with ovalbumin. The relations between plasma lipid concentrations, atherosclerotic lesions, and cytokine production and proinflammatory stimuli or foreign antigens were characterized. Phytosterol-enriched diets were strongly associated with reduced plasma cholesterol concentrations and atherosclerosis in conjunction with higher anti-inflammatory [interleukin (IL)-10] and lower proinflammatory cytokine [IL-6, tumor necrosis factor (TNF)-alpha] production. In contrast, development of cytokine and chemokine responses to ovalbumin was as strong as or even improved in the phytosterol-treated mice relative to controls. The antiatherogenic effects of dietary phytosterols in apo E-knockout mice were associated with beneficial alterations in both lipoprotein metabolism and inflammatory pathways. Decreased capacity to mount proinflammatory cytokine and chemokine responses to inflammatory stimuli did not interfere with the global immunocompetence of such mice. Thus, the desirable suppression of proinflammatory cytokine production that was associated with inhibition of atherogenesis did not impair the capacity to mount responses to foreign antigens.