Murine gammaherpesvirus is a natural pathogen of wild rodents. In the laboratory it establishes an infection of epithelial cells and persists in B lymphocytes in a latent form. Inbred mice chronically infected with the virus develop a lymphoproliferative disease (LPD) similar to that seen in patients infected with Epstein-Barr virus. The frequency of LPD over a period of 3 years was 9% of all infected animals, with 50% of these displaying high grade lymphomas. The incidence of LPD was greatly increased when infected mice were treated with cyclosporin A. The majority of mice used in the experiments were BALB/c, although lymphomas were detected in mice on other genetic backgrounds, ie, CBA and B10Br. Lymphomas were associated with both lymphoid and nonlymphoid tissues (liver, lung, and kidney). In all cases of lymphomas studied thus far, there was a mixed B cell (B220+ve) and T cell (CD3+ve) phenotype. The B cells were light chain restricted, indicative of a clonal origin. Variable numbers of virus genome-positive cells were detected by in situ hybridization in and around the lymphomas. In contrast, no lytic antigen-positive cells were detected, indicating that genome-positive cells were either latently infected or undergoing an abortive infection. These observations suggest that murine gammaherpesvirus-infected mice may be an important model to study the pathogenesis of LPD associated with other gammaherpesviruses, such as Epstein-Barr virus.