In the 30-month period from January 1987 through June 1989, 57 patients underwent heart transplantation. Immunosuppressive therapy consisted of a combination of cyclosporine, azathioprine, low-dose methylprednisolone, and antilymphoblast globulin. Clinically significant, proven cytomegalovirus (CMV) disease has developed in no fewer than 22 patients (39%), involving the lung (n = 11), colon (n = 8), stomach (n = 4), and retina (n = 1). The diagnosis was confirmed by direct fluorescent antibody (DFA) (n = 14), histologic study (n = 6), and culture (n = 6) in all cases. The onset of CMV infection occurred at a mean of 5.7 months after heart transplantation (range, 3 weeks to 18 months). All patients were treated with ganciclovir until no sign of active CMV disease could be found. The length of treatment required varied from 2 to 8 weeks (mean, 3.5 weeks). Recurrence has occurred in only one patient, necessitating a further 26-week course of therapy. There were no deaths attributed definitely to CMV disease. There was a higher incidence of acute rejection in the first 3 posttransplant months (0.68 episodes/patient) in the CMV group than in those in whom CMV disease did not develop (0.34 episodes/patient; p < 0.02). Of the CMV patients, 25% had significant features of fraft atherosclerosis during the first posttransplant year, compared with only 8% of the non-CMV patients. In conclusion, (1) there was a high incidence of CMV disease with this immunosuppressive regimen, and we have subsequently discontinued routine antilymphoblast globulin therapy and instituted a triple therapy immunosuppressive protocol with prophylactic immunoglobulin and acyclovir; (2) CMV disease was successfully treated in all cases with ganciclovir alone; and (3) there was a trend toward an increased incidence of both acute rejection and accelerated graft atherosclerosis in the CMV group of patients.