Efficacy of recombinant DNA-derived murine IFN-gamma was investigated in a murine model of cytomegalovirus infection. Treatment of 3-week-old Swiss Webster mice with murine IFN-gamma prior to infection with murine cytomegalovirus (MCMV) significantly reduced mortality due to MCMV infection. Efficacy was dose-dependent and was observed using either intraperitoneal or intramuscular injection as the route of administration. Two doses, one at 24 h and one at 4 h prior to MCMV infection, were required for optimum efficacy, and doses administered after MCMV infection had no apparent effect. Reduced infectious MCMV titers were observed in critical organs of IFN-gamma treated mice and histopathologic lesions induced by MCMV infection were in general less severe and resolved sooner than lesions in untreated mice. Results in this murine model of cytomegalovirus infection suggest that IFN-gamma treatment may be useful as prophylactic therapy for human cytomegalovirus infections when a high probability of exposure to the virus exists and consequences of infection may be severe.