There is considerable interest in developing viral vaccines intended to induce T cell immunity, especially cytotoxic CD8+ T lymphocytes, when Abs are not protective or are too narrow in viral strain specificity. We have studied protective immunity in doubly inactivated (DI) mice devoid of Abs and mature B cells. When infected with influenza B virus, these mice cleared the virus in a process dependent upon CD8+ T lymphocytes. Cytotoxic activity was detected in lung lymphocytes of DI mice after primary or secondary infection, and was abrogated by depletion of CD8+ cells in vivo. Challenge experiments showed that DI mice could be protected by immunization against reinfection 1 mo later, and protection was virus specific. Depletion of CD4+ or CD8+ T cells in vivo during the challenge period partially abrogated, and depletion of both subsets completely abrogated, the protection. This indicates that both CD4+ and CD8+ T cells are required effectors in the optimal control of virus replication. Thus, when Abs fail to protect against varying challenge viruses, as is the case with variant strains of influenza and HIV, there is hope that T cells might be able to act alone.