Human alveolar macrophages (HAM) from 28 normal volunteers were found to inhibit replication of Cryptococcus neoformans. Conditions under which fungistasis occurred were different than those required for mouse peritoneal macrophage-mediated fungistasis. Inhibition of fungal replication by mouse peritoneal macrophages (MPM) requires that the macrophages are activated and that the cocultures of C. neoformans and macrophages be done in the presence of serum, L-arginine, and endotoxin. HAM-mediated fungistasis was not enhaced by endotoxin or by recombinant human interferon-gamma (rHIFN-gamma). The combination of endotoxin and rHIFN-gamma inhibited the fungistatic effect of HAM. Human peritoneal macrophages (HPM) from women undergoing laparoscopy were tested for fungistasis and L-arginine nitrogen oxidation. Partial inhibition of cryptococcal replication occurred; however, there was no evidence of L-arginine metabolism to NO2- or NO3-. The absence of L-arginine-dependent nitrogen oxidation in HAM and HPM, compared to MPM, during conditions under which fungistasis occurs suggests that the phenomenon is species specific rather than specific to the tissue origin of the macrophages.