Murine gammaherpesvirus (MHV-68) causes an acute respiratory infection followed by a latent infection in B lymphocytes. In the first 2-3 weeks after infection mice develop a marked splenomegaly, where the spleen cell number increases by 2-3 fold. Cytofluorimetric analysis during splenomegaly revealed an increase in numbers of B lymphocytes and of both CD4+ and CD8+ T lymphocytes. The largest increase relative to uninfected spleens was in the CD8+ population. The number of latently infected cells in the spleen peaked at day 10 post-intraperitoneal infection, then declined to 1/10(6)-1/10(7) cells per spleen. Depletion of CD4+ T lymphocytes prevented the splenomegaly and greatly reduced the peak infective centre level, while having no effect on the long-term of latently infected cells. Given the similarity between MHV-68-induced splenomegaly and Epstein-Barr virus-induced infectious mononucleosis, these data highlight the usefulness of MHV-68 as a mouse model for the study of gammaherpesvirus immunology and pathobiology.