To determine if the oxygen-dependent and -independent antiprotozoal mechanisms with which the human mononuclear phagocyte is equipped to act against Leishmania donovani operate against other intracellular parasites, oxidatively intact and deficient cells were challenged with Toxoplasma gondii. Fresh monocytes and lymphokine- or gamma-interferon (IFN-gamma)-activated macrophages from normal individuals killed 35% and 50% of T. gondii within 6 hr, respectively, and each of these cell populations inhibited the replication of surviving parasites 20 hr after infection. This activity was associated with the capacity to release large amounts of H2O2 (572 to 971 nmol/mg) and to respond to toxoplasma ingestion with respiratory burst activity. Impairing the ability to generate oxygen intermediates by glucose deprivation or treatment with superoxide dismutase, catalase, or mannitol inhibited toxoplasmacidal activity by greater than 80% and permitted a 2.6- to 4.3-fold increase in the number of intracellular toxoplasmas. In contrast to normal cells, fresh monocytes from patients with chronic granulomatous disease (CGD) killed less than 8% of toxoplasmas and exerted 50% less toxoplasmastatic activity. However, although associated with the induction of only modest toxoplasmacidal effects (18 to 20% killing), lymphokine stimulation did induce CGD monocytes and macrophages as well as oxidatively inactive human endothelial cells to display near normal levels of toxoplasmastatic activity. Similar to oxygen-dependent mechanisms, the enhancement of oxygen-independent activity by crude lymphokines could be abolished by a monoclonal anti-IFN-gamma antibody and could be achieved by treatment with recombinant IFN-gamma alone. Unstimulated CGD monocytes, however, were found to lose all antitoxoplasma activity after two days in culture, whereas normal cells continued to effectively inhibit T. gondii replication, suggesting that oxygen-independent responses may not actually be required for the normal monocyte to act against T. gondii. Taken together with previous findings with L. donovani, these results indicate that the human mononuclear phagocyte possesses an oxygen-independent antiprotozoal mechanism and that its effects can be enhanced by lymphokines (IFN-gamma), but that nevertheless this cell's primary response to intracellular protozoa is largely oxygen dependent.