Infection with herpes simplex virus is common among immunosuppressed patients. In an attempt to prevent such infection, 58 patients (group 1) who underwent cardiac transplantation between 1987 and 1990 were given acyclovir (200 mg orally three times a day) prophylactically throughout their postoperative hospital stay (mean 22 days +/- 1 day). The patients' immunosuppressive protocol included cyclosporine, azathioprine and prednisone. The course of these patients was compared to that of 24 patients (group 2) who underwent cardiac transplantation between 1983 and 1986 but were not given prophylactic antiviral treatment postoperatively. The immunosuppressive protocol in these patients consisted of cyclosporine and prednisone. Herpes infection developed during the 1st year in 5 patients (9%) in group 1 and in 11 patients (46%) in group 2 (p < 0.05). The actuarial rates of freedom from herpes infection at 1, 6 and 12 months after transplantation were 100%, 98% +/- 2% and 95% +/- 3%, respectively, in group 1 and 82% +/- 7%, 58% +/- 11%, 53% +/- 11% in group 2. All viral infections were cutaneous or mucosal, except for one, which developed in a patient with pneumonia. All infections responded well to treatment, although one patient with an infected cornea was left with a permanent visual deficit. The authors conclude that prophylaxis of herpes simplex virus infection with acyclovir administered orally in the early postoperative period is effective in preventing viral infections during the 1st year after cardiac transplantation.