The oxidative metabolism of monocytes and polymorphonuclear leukocytes from human peripheral blood was studied in resting and phagocytosing cells. Monocytes, like neutrophils, showed an increase in oxygen consumption during phagocytosis with a concurrent release of superoxide anions and hydrogen peroxide. Both oxygen products are highly reactive agents with potential bactericidal activity. Neutrophils consumed two and a half times as much oxygen, generated about twice as much superoxide, and released five times as much hydrogen peroxide as monocytes did. Monocytes generated superoxide and hydrogen peroxide at equivalent rates.Antimycin A, a specific mitochondrial respiratory chain inhibitor, depressed the oxygen consumption of monocytes by congruent with70% but had no effect on neutrophil respiration. Therefore, the oxygen consumed by phagocytosing monocytes appeared to be metabolized in two distinct processes: congruent with30% of the oxygen is converted to hydrogen peroxide, whereas the remaining 70% is metabolized via the mitochondrial respiratory chain. The release of superoxide and hydrogen peroxide was unaffected by antimycin in either cell type. Phagocytosis of zymosan particles by monocytes was nearly abolished by antimycin, whereas no effect was noted with neutrophils. Thus, phagocytosis appears to be highly dependent on oxidative phosphorylation in monocytes but not in polymorphonuclear leukocytes. Moreover, in monocytes treated with antimycin, an addition of opsonized zymosan particles induced stimulation of the oxidative metabolism without occurrence of ingestion.