The efficacy of oral acyclovir to prevent reactivation of herpes simplex virus (HSV) in seropositive renal allograft recipients was tested in a double-blind placebo controlled study. None of the 18 patients allocated to acyclovir showed any signs of HSV infection. In contrast, 11/17 on placebo (p less than 0.001), had signs of HSV or varicella zoster virus (VZV) infection--in 5 patients severe enough to interrupt the trial and initiate treatment with oral acyclovir. Soon after cessation of the trial, HSV was isolated from the throats of 6 patients on acyclovir, and 1 developed shingles 3 months later. Oral acyclovir prophylaxis thus effectively protected the patients from reactivation of HSV and VZV while they were receiving the drug, but could not prevent disease once off the drug. Treatment with acyclovir brought rapid relief of both local and general symptoms in all patients. No adverse reactions were seen. As a consequence of these experiences our goal in subsequent transplant patients has been either early therapeutic intervention with oral acyclovir whenever signs of HSV or VZV infection have been noted, or prophylactic remedy in patients at particular risk to develop troublesome herpetic lesions after renal transplantation.