This study compares the pathogenesis of murine cytomegalovirus (MCMV) infections following intraperitoneal (I.P.) and intratracheal (I.T.) inoculation. No deaths were seen in mice given 1,000,000 pfu MCMV I.T., whereas 52% mortality occurred among animals given this dose I.P. This difference in mortality was not due to different effects on the lung since virus titers in this organ on progressive days post-infection were similar for the 2 routes of inoculation and similar, minor histopathologic changes were observed. In contrast, virus titers in the livers of mice inoculated I.P. were 100 fold higher than for those inoculated I.T., and histopathologic changes were noticeably greater in the I.P. group. Effects on liver function are the most likely explanation for the mortality seen following I.P. inoculation. Parallels between various forms of human cytomegalovirus infections and the types of infections seen following I.T. and I.P. MCMV infection were observed.