The course of Sindbis virus infection in 12-day-old BALB/c mice was altered significantly in animals depleted of the third component of complement (C3) by treatment with purified cobra venom factor (CoVF). Although the same percentage of C3-depleted and normal animals died (30%) after the subcutaneous inoculation of 1000 PFU Sindbis virus, the mean day of death was later in C3-depleted mice (8.4 days) than in controls (6.5 days). In addition, morbidity was prolonged in C3-depleted mice. Growth of virus at the inoculation site in the foot was not different; however, viremia was prolonged and the amount of virus in the brain was 1000-fold greater 6 days after infection in C3-depleted animals. These studies demonstrated that complement plays an important role in the host's response to Sindbis virus infection by participating in both beneficial and immunopathologic responses to the infection.