To elucidate the role of class switch recombination (CSR) and somatic hypermutation (SHM) in virus infection, we have investigated the influence of the primary and secondary infections of influenza virus on mice deficient of activation-induced cytidine deaminase (AID), which is absolutely required for CSR and SHM. In the primary infection, AID deficiency caused no significant difference in mortality but did cause difference in morbidity. In the secondary infection with a lethal dose of influenza virus, both AID^−/− and AID^+/− mice survived completely. However, AID^−/− mice could not completely block replication of the virus and their body weights decreased severely whereas AID^+/− mice showed almost complete prevention from the reinfection. Depletion of CD8⁺ T cells by administration of an anti-CD8 monoclonal antibody caused slightly severer body weight loss but did not alter the survival rate of AID^−/− mice in secondary infection. These results indicate that unmutated immunoglobulin (Ig)M alone is capable of protecting mice from death upon primary and secondary infections. Because the titers of virus-neutralizing antibodies were comparable between AID^−/− and AID^+/− mice at the time of the secondary infection, a defect of AID^−/− mice in protection of morbidity might be due to the absence of either other Ig classes such as IgG, high affinity antibodies with SHM, or both.