When adult mice were injected by the footpad route with the attenuated rabies virus ERA/BHK, serum- and brain-associated antibody and interferon were produced, nonspecific cytotoxic cells and virus-specific cytolytic T cells in the spleen were activated, and a nonlethal infection of the central nervous system occurred. Cyclophosphamide treatment of these animals 1 day after virus infection suppressed antibody formation and induction of cytolytic T cells and resulted in a lethal infection. Virus injection into athymic mice also produced lethal infections. This indicated the importance of the T-cell response in survival but did not allow the response of cytolytic T cells to be distinguished from that of helper T cells. because cyclophosphamide has a longer-lasting effect on B cells than on T cells, the resulting mortality when virus is injected at intervals after cyclophosphamide treatment can be used to distinguish the importance of each of these cells in viral clearance. Although delay of rabies virus ERA/BHK injection until 3 days after cyclophosphamide treatment resulted in induction of a strong cytolytic T-cell response and reduced mortality, the mortality could be further reduced by delaying virus infection until the B-cell response had recovered. This indicated that both humoral and cellular immune components were vital for survival in this model.