A group of 132 renal transplant recipients were systematically screened for viral infections and the findings correlated with the clinical course. 110 patients showed evidence of infection with herpesviruses and 89 patients showed laboratory evidence of infection with cytomegalovirus (CMV) uncomplicated by bacterial infections or technical difficulties. Patients without viral infections were usually asymptomatic. After recovery and development of viral antibodies, most patients were asymptomatic despite the persistence of viral excretion in the urine. In contrast, the onset of viral infections was almost always accompanied by a significant clinical illness characterized by fever, leukopenia, and renal malfunction. Of 89 patients with cytomegalovirus infections, 83 survived for at least three months. In these patients, the fever appeared to be self limited and resolution of the fever was accompanied by increases in anti CMV antibody. Renal biopsies demonstrated typical rejection reactions in all the biopsied patients and renal malfunction usually responded to anti rejection treatment. Six of the 89 patients with CMV infections died within a month of viral isolation. These patients could be distinguished from those who recovered by a decreased or absent antibody response to the virus, suppressed lymphocyte responses to mitogen in autochthonous blood and absent histologic evidence of rejection in the renal allografts. Thus, two paradoxical responses to CMV infections are seen in transplant patients: In the relatively immunocompetent patient, the infection is associated with renal allograft rejection, a prompt antibody response to the virus, and recovery. The severely immunosuppressed patient cannot make an antibody response, and does not exhibit allograft rejection as a cause of renal malfunction; he may be further immunosuppressed by the viral infection, and is susceptible to sequential opportunistic infections leading to death.