Newborn germ-free (GF) and conventional (CV) BALB/c mice were infected with murine leukemia virus-Moloney (MuLV-M) and subsequently monitored for virus expression and leukemia development. GF mice expressed more than 10-fold less virus in peripheral blood compared with CV mice, despite equivalent numbers of infected cells in the spleens, lymph nodes, thymi, and bone marrow of both groups. In addition to lower levels of virus expression, the latency period before the onset of fatal leukemias was greatly extended in GF mice; the first and last fatalities were recorded at 25 and 43 weeks postinfection, respectively, with a mean survival time of approximately 36 weeks. In CV mice, the first and last fatalities occurred at 8 and 17 weeks, respectively, with a mean survival time of approximately 13.5 weeks. Finally, the gross pathology of involved lymphoid organs varied in the two groups. GF mice experienced severe splenomegaly with or without lymphadenopathy but without thymoma; CV mice, in contrast, developed splenomegaly, lymphadenopathy, and severe thymoma. Collectively, these results indicate a marked resistance of GF animals to MuLV-M and suggest that the level of immune system activation may influence the pathogenicity of nontransforming retroviruses.