The relationship between herpes simplex virus (HSV) infection and specific cellmediated immunity was investigated in 141 patients before and for the first four months after marrow transplant. Sixty-two (82%) of 76 seropositive patients but only one of 65 seronegative patients developed HSV infection. Lymphocyte responses to HSV antigen were suppressed immediately after transplant and subsequently became reactive in those patients with HSV infection. The presence or absence of antibody to HSV in the donor before transplant did not influence the response. Seventy long-term survivors of marrow transplant were also studied. Among 60 patients who had pretransplant serum available for study, 26 (68%) of 38 who had been seropositive before transplant had positive responses compared with none of 22 who had been seronegative. Recovery of responsiveness to HSV antigen after marrow transplant is primarily related to recurrent virus infection and not to the pretransplant immune status of the donor.