MHV(PRI) virus produced a non-fatal immunizing infection in adult C3H mice over a greater than 6.0 log10 unit range but a uniformly fatal infection in adult Princeton (PRI) mice. Neonatally thymectomized 4-6 wk old C3H mice died by day 10 after inoculation with MHV(PRI). Intact and thymectomized C3H mice had comparable virus titers in their livers until day 7 postinfection, after which time virus was undetectable in intact C3H mice but remained at high titers in thymectomized C3H mice. The liver pathology was similar in both groups until day 6 post infection, after which time resolving lesions were seen in livers of intact C3H mice; whereas thymectomized C3H mice developed fulminant fatal hepatitis. In in vitro tests, the macrophages of the thymectomized C3H mice did not support growth of MHV(PRI) virus to any greater extent than the macrophages of nonthymectomized C3H mice. Although infection with MHV(PRI) was fatal for both PRI and thymectomized C3H mice, the course of infection was much more rapid in PRI mice. C3Hss mice, which are congenic with C3H mice but have macrophages which support growth of MHV(PRI), responded to MHV(PRI) infection with a rapidly fatal illness in the same way as PRI mice. Macrophages resistant to viral multiplication and intact thymic function are probably both necessary for resistance to the lethal effects of MHV(PRI) virus.