This study was conducted to determine the incidence and clinical significance of human herpesvirus-6 (HHV-6) infection in renal allografts. A total of 105 biopsy specimens from 72 recipients were immunohistochemically examined for the presence of HHV-6 antigen, which localized in the distal tubular epithelial cells and in a few lymphocytes infiltrating into the interstitium. HHV-6 antigen in the tubular epithelia was detected in 63 (61.2%) specimens. Categorically, a higher incidence of the antigen was noted in specimens of accelerated rejection (3/4, 75.0%), acute rejection (28/3, 73.7%), and cyclosporin nephropathy (8/11, 72.7%). The antigen was present and absent an almost equal number of times in the categories of chronic rejection, intraoperative and routine protocol biopsies. Repeated biopsies were performed in six cases showing HHV-6 antigen, only one of which underwent transplant nephrectomy due to severe chronic rejection. Single or multinucleated giant cells in distal tubuli occurred in 10 (9.5%) specimens in a scattered manner. All of them were diagnosed as acute or chronic rejection. The giant cells showed no immunoreactivity for HHV-6, cytomegalovirus, or herpes simplex virus. These results indicate overall that HHV-6 infection is common in renal allografts and might be reactivated in acute rejection or cyclosporin nephropathy. The presence of HHV-6 antigen, however, does not necessarily correlate with a poor prognosis for the renal graft nor with the occurrence of giant cells in distal tubuli.