The effect of hyperlipemic human serum on superoxide anion (O2−) production by rat peritoneal macrophages was investigated. Phorbol myristate acetate (PMA)-stimulated O2−production was inhibited when cells were preincubated with hyperlipemic human serum. This inhibition was specifically carried out by a lipid fraction and was dependent on both cholesterol and triglyceride serum levels. This inhibitory effect was not exerted by a direct effect on NADPH-oxidase activity, nor by a putative superoxide dismutase activity present in the serum. With human neutrophils, we observed a decreased mobility of the cytosolic factor p47-phox to the membrane during the activation process, caused by hyperlipemic serum. We did not find any effect of hyperlipemic serum on NO2−production by cultured rat macrophages. These results suggest that a pathological increase of circulating plasma lipids may be associated with an impaired inflamatory capacity of macrophages.