Forty patients were prospectively studied for infection with cytomegalovirus (CMV) and herpes simplex virus (HSV) after renal transplantation. Although 85% had antibody to CMV and 95% had antibody to HSV prior to transplantation, excretion of CMV was found in 92.5%, usually as viruria, and HSV was recovered from 70%, most often from the oropharynx. Shedding of HSV reached a peak within the first month after transplantation when immunosuppression was most intense and then rapidly declined. In contrast, excretion of CMV was found in a greater proportion of patients during each interval up to about six months after transplantation and subsequently persisted in the majority of patients. Both serologic responses and viral isolation rates indicated more rapid activation of CMV but not of HSV in recipients of kidneys from cadavers than in patients who received kidneys from living related donors. At 60 days after transplantation, 76% of the recipients of kidneys from cadavers and only 33% of the recipients of kidneys from living, related donors had shed CMV (P = 0.003). These differences could not be accounted for by immunosuppressive treatment. Excretion of HSV was clearly associated with the time of most intense immunosuppression, but the major factor in initiation and maintenance of productive infection with CMV appeared to be the host vs. graft reaction.