SUMMARY Because of the ubiquity of cytomegalovirus (CMV) infection among renal transplant patients, the correlation between CMV isolation and clinical events is often difficult. In this prospective study, clinical CMV disease was diagnosed in 26 of 68 patients (38%) that received transplants between 1974 and 1976 on the basis of viral isolation and/or >4-fold rise in complement-fixing antibody in patients with an unexplained febrile illness of >5 days' duration. All CMV syndromes began 1 to 4 months post-transplant, persisting up to 23 weeks thereafter (mean duration of symptoms was 19 days). Although CMV was observed in some instances to cause only prolonged fever (10 patients) or hepatitis (4 patients), its most important effects were pneumonia (9 patients) and profound leukopenia (8 patients). Three patterns of pneumonia were observed: bilateral interstitial pneumonia (3 patients), unilateral focal consolidation (1 patient) (both attributable to CMV alone), and diffuse bilateral pneumonia attributable to CMV and superinfecting microorganisms (5 patients). These last patients had CMV-induced leukopenia of >1 week's duration at onset of superinfection, and all died. The 4 patients without leukopenia did not develop superinfection, and all survived. Two other renal transplant recipients died of infection during this period, both with CMV, leukopenia, and Listeria monocytogenes sepsis. The major infectious disease importance of CMV appears to be its effects on the respiratory tract and systemic host defense in predisposing to fatal superinfection.