The course of an intranasal infection of Sendai virus in CBA and DBA mice was investigated in animals decomplemented with purified cobra venom factor. The mice were decomplemented either immediately before inoculation or at 4 days postinfection. Depletion of complement after the infection had been established had no apparent effect on the course of the viral infection in the two strains of mice. In contrast, both strains of mice were protected completely from the lethal effects of an infectious dose of 1 LD50of virus when the serum C3 levels were depressed by more than 80% during the early stages of infection. The symptoms of morbidity were less pronounced in these animals and there was a delay in the production of hemagglutination-inhibiting antibody. There was no apparent effect on the growth of the virus in lung tissue. The results suggest that the complement system plays a significant pathogenic role during the course of Sendai virus infections in CBA and DBA mice.