The effects of cocaine on the respiratory burst (RB) and the phagocytic activity of murine macrophages (M phi) were studied. C57BL/6 mice were injected intraperitoneally with various concentrations of cocaine or appropriate vehicle. Peritoneal and alveolar M phi were isolated from mice and cultured in vitro. Both alveolar and peritoneal M phi from cocaine-exposed mice exhibited an increase in the RB when compared with M phi from saline-injected controls. This increase in the RB was apparent 60 min after injection and persisted for at least 48 hr. Injection of the cocaine metabolites, ecgonine methyl ester hydrochloride and ecgonine hydrochloride, did not affect the RB. The increase in the RB was correlated with an increase in phagocytosis of opsonized zymosan in vitro. However, an in vivo phagocytic assay using mice injected ip with cocaine, which was subsequently followed by sheep erythrocytes, demonstrated the opposite effect. Fewer peritoneal M phi from cocaine-injected mice were observed with ingested erythrocytes. These data underscore the complex effects of cocaine on M phi functions.