The resistance of mice to intraperitoneal and intramuscular infection with fixed rabies virus increases with age. Treatment of mature animals with either silica, indian ink or antimacrophage serum, which are cytotoxic for macrophages, reduced their resistance to intraperitoneal, but not to intramuscular or intracerebral infection. Transfer of peritoneal macrophages from adults to syngeneic suckling mice delayed but did not prevent mortality from intraperitoneal infection: transfer of peritoneal macrophages to intramuscular sites of infection did not protect adult mice. Rabies virus was phagocytosed by peritoneal macrophages in culture but neither replicated nor induced interferon. Evidence of active intracellular destruction of virus was obscured by thermal inactivation at 37 degrees C. Less inactivation occurred at 33 degrees C. Infected macrophages from suckling mice, but not those from adult mice, spread infection to susceptible cells.