Mice were studied for 3 to 4 months after murine cytomegalovirus (MCMV) infection. Serial hematological parameters were evaluated. It was found that MCMV infection of mice were accompanied by the appearance of many atypical lymphocytes similar to those seen in association with the hematological features of mononucleosis associated with human CMV infection. Certain functions of splenocytes were studied in infected and uninfected animals during the 4 months after MCMV infection. Three periods were identifiable by the functional response of splenocytes during the course of MCMV infection. The initial phase was characterized by an elevated response of splenocytes to a T cell mitogen and a B cell mitogen (phytohemagglutinin and lipopolysaccharide, respectively). The intermediate phase was marked by productive virus replication in the salivary gland, injury to lymphoid elements, a depressed response of splenocytes to mitogens (phytohemagglutinin and lipopolysaccharide), and decreased humoral splenocytes to phytohemagglutinin stimulation was again increased, and a nonproductive latent infection was established. Study by scanning electron microscopy of splenocytes during the course of infection revealed morphological changes which were correlated with functional alterations.