Bacille Calmette-Guerin (BCG) has been used effectively to protect nonspecifically against bacterial infections and neoplasms, probably by enhancement of cell-mediated immunity. It has been suggested that cell-mediated immunity plays a role in the host defense against certain viral infections. In recent in vitro studies, macrophages from animals sensitized by BCG were more effective in lowering the titer of influenza virus than were macrophages from control animals. The purpose of this study was to investigate the in vivo effectiveness of nonspecific immune stimulation with BCG on influenza virus infection in mice. Immunization with BCG resulted in significant protection of mice. Also, the local (nasal) route of immunization was more effective than the systemic (intraperitoneal) route against the intranasal inoculum of virus, a finding which suggests the important role of local immunity, i.e., either earlier stimulation of secretory antibody or nonspecific cell-mediated immunity. The time course of the resistance to infection suggests that interferon was not the protective mechanism.