BACKGROUND Systemic viral disease after renal transplantation, especially after treatment with OKT3 or antithymocyte globulin, has usually been attributed to cytomegalovirus (CMV) infection. Identification of human herpesvirus 6 (HHV6) has raised the possibility that infection or reactivation of this virus may also occur in the same setting. METHODS We thus examined the incidence of CMV and HHV6 infection in a prospective blinded consecutive series of 30 renal and renal/pancreas transplant patients, 22 of whom received OKT3, antithymocyte globulin, or both. RESULTS Clinical diagnosis of a viral syndrome was made in 15 patients. Three patients with only HHV6 DNA in urine or serum had fever and abnormal liver function but not neutropenia. All five CMV-seronegative patients who received positive kidneys developed moderate to severe disease with fever and neutropenia but also had HHV6 DNA in urine or serum. Seven CMV-seropositive patients developed disease, mostly after OKT3/antithymocyte globulin, but six shed both CMV and HHV6 in urine or serum. The simultaneous detection of both HHV6 and CMV DNA in either urine or serum was the strongest predictor of disease (and also the severity of disease), with an odds ratio of 99.0 (95% confidence intervals 5.4-1814, P<0.002). CONCLUSIONS Most systemic viral disease after renal transplantation may be due to either coinfection or reactivation of CMV and HHV6 together. A wider understanding of risk factors for severe viral disease in this setting may come from testing for both viruses in all donors and patients in both clinical practice and clinical trials.