Spleens from C3D2F1 mice acutely infected with murine cytomegalovirus (MCMV) were examined for mechanisms of viral clearance and alteration of immune function. Inclusion-bearing cells in the perifollicular marginal zone were found to peak at Day 3 after infection and to be associated with infiltrates of polymorphonuclear leukocytes (PMNs). Inclusions and PMNs were cleared by Day 6. Hematopoietic islands, although not impinged upon, could not be found by Day 3 after infection but reappeared and were considerably enlarged by Day 6. Most importantly the T-dependent areas of the spleens revealed no viral inclusions and no lysis. Stimulated morphology was seen in T-dependent areas by Day 1 after infection and remained so for over 3 weeks. T-independent areas contained germinal centers at Day 4 and thereafter. Therefore, in the absence of viral cytopathologic features in the T-dependent and T-independent areas, other mechanisms must account for the immunosuppression observed during acute infection. The observations of an activated morphology are compatible with other data demonstrating an alteration in immunoregulation as the mechanism for the immunosuppression associated with MCMV infection.