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The mechanisms and importance of the Fc portion of immunoglobulin on experimental atherosclerosis in apolipoprotein E-deficient mice were examined. Experimental atherosclerosis was induced in mice fed a high fat diet containing 0.3% cholesterol. Over eight and 16 weeks, the mice were treated with intraperitoneal injections (1 g/kg/day) of either human intact immunoglobulin or F(ab')(2) fragments of human immunoglobulin on alternate days. Fatty streak formation and fibrofatty plaques were markedly suppressed in mice that received intact immunoglobulin for eight and 16 weeks. In contrast, atherosclerotic lesions did not improve in mice that received F(ab')(2) fragments. Differences in lesion area did not correlate with any significant alterations in serum lipid levels. Immunoglobulin therapy markedly suppressed atherosclerosis due to Fc receptor-mediated anti-inflammatory and immunomodulating actions.