The routine use of monoclonal induction immunosuppression with OKT3 after orthotopic heart transplantation remains controversial. This study examined the clinical response of prophylactic monoclonal induction immunosuppression versus standard triple-drug immunosuppression in 41 patients who underwent orthotopic heart transplantation from January 1989 to December 1990 at this institution. Of these, eight received monoclonal induction immunosuppression for a period of 10 to 14 days. All patients received identical triple-drug immunosuppression with the exception of cyclosporine starting on the fifth postoperative day in those who received OKT3. At 6 months the duration of hospitalization, freedom from rejection, incidence of infection requiring hospitalization, and serum creatinine in the monoclonal induction immunosuppression and triple-drug groups were compared. It was found that the length of hospital stay in the OKT3 group was 14.3 ± 4.5 days, compared with 14.7 ± 4.7 days in the triple-drug group and that freedom from rejection was 66% in the OKT3 group compared with 75% in the triple-drug group. In addition, it was found that the incidence of infection was 36% in the OKT3 group compared with 38% in the triple-drug group and that serum creatinine at 6 months was 1.36 ± 0.26 mg/dl in the OKT3 group compared with 1.45 ± 0.73 mg/dl in the triple-drug group. Finally, patient survival at 1 year for the monoclonal induction immunosuppression group was 100% compared with 91% for the triple-drug group. It was concluded that induction immunosuppression with monoclonal induction immunosuppression does not reduce the duration of hospitalization or the incidence of rejection, change the incidence of infection, alter renal function, decrease the incidence of allograft coronary artery disease, or improve the survival rate as compared with standard triple-drug immunosuppression.