Herpes simplex virus (HSV) reactivation and lesion formation were studied in 68 renal transplant recipients and 30 leukemic patients. Antibody titers to HSV were determined, and seropositive patients were examined three times weekly for up to one month. Surveillance cultures were taken for oral HSV, and HSV culture and cytology were done for all oral lesions found. In a smaller number of patients, immune responses were determined. HSV reactivation was similar in the transplant and leukemic groups (46.8% vs. 50%), but a significant difference in the incidence of HSV lesion formation was noted between the two groups. Of the transplant patients in whom HSV reactivated, 31.8% developed HSV lesions; of leukemic patients in whom HSV reactivated, 100% developed HSV lesions. Differences in the incidence of formation of HSV lesions in these groups of immunosuppressed patients suggest that reactivation of HSV and formation of HSV lesions may involve different mechanisms. Low levels of antibody-dependent cellular cytotoxicity were noted in leukemic patients and may contribute to increased formation of HSV lesions in this group.