In virus-positive (V+) C57BL/6 Mov-13 mice, Moloney-murine leukemia virus (M-MuLV) is integrated into the germ line and expressed early in lymphoid and nonlymphoid organs. The pattern of immune reactivity to viral antigens in these mice was studied and compared to that of their virus-negative (V-) counterparts. Using a radioimmuno-binding or -precipitation assay, V- mice showed good antibody production after challenge with Moloney-murine sarcoma virus (M-MSV), but no antibodies were detected in V+ mice. Moreover, Mov-13 V+ mice failed to generate virus-specific cytotoxic T lymphocytes (CTL) in secondary mixed-leukocyte tumor cell culture (MLTC) while V- mice showed a strong cytotoxic response. This lack of activity in mass V+ cultures was due to a very low frequency of CTL precursors which did not increase following in vivo challenge with M-MSV or in vitro stimulation with MBL-2 Moloney leukemia cell line. These findings indicate that early M-MuLV activation in Mov-13 V+ mice induces a state of tolerance to viral antigens involving both the humoral and cellular immune responses and related to the high incidence of T-cell lymphomas.