Acute myocardial rejection refractory to treatment still contributes significantly to patient death after intrathoracic transplantation. A historical series of 25 patients who received OKT3 (5 mg/day for 10 days) was compared with our current experience with 14 patients treated with tacrolimus (0.1 mg/kg/day targeting whole blood concentrations of 13 to 18 ng/ml): all 39 patients having persistent rejection unresponsive to treatment at the time of conversion. Mean periods of follow-up were 842.9 days and 342.6 days, respectively. Actuarial 1-year patient survival rates were 64.0% and 76.2% for the OKT3 and tacrolimus treatment groups, with most of the deaths in the OKT3 group occurring early (p = 0.064). Causes of death for patients receiving OKT3 included acute rejection (n = 5), infection (n = 3), carcinoma (n = 2), multiorgan failure (n = 1) and graft vessel disease (n = 1). The two deaths in the tacrolimus treatment group were the result of infections. Eighty percent of patients treated with OKT3 subsequently experienced further rejection episodes, in many cases necessitating methotrexate therapy. In contrast, only one patient (7.1%) from the tacrolimus group was diagnosed with rejection after conversion (p < 0.001). In conclusion, when compared with OKT3 therapy, a switch in baseline immunosuppression from cyclosporine to tacrolimus seems to be markedly more effective, as well as being safe for the treatment of persistent acute rejection.