C5-deficient (C5-) mice succumb much sooner after intravenous inoculation with Cryptococcus neoformans than do C5-sufficient (C5+) mice. The C5- mice developed acute, fatal cryptococcal pneumonia, whereas the C5+ mice did not. The pneumonia was characterized by lung viable counts in C5- mice up to 1000-fold higher than in C5+, initial sequestration of twice as much 59Fe-labeled C. neoformans, and subsequent development of pulmonary edema. Chemotaxis of heterophils (PMNs) and mononuclear cells in response to C. neoformans was markedly greater in C5+ mice than in C5- animals. The effect of C5 on localization and growth of C. neoformans in the lung appeared to account for the disparate survival times of C5+ and C5+ mice after intravenous inoculation with C. neoformans.