The present analysis of risk factors in human cardiac transplantation is based on a review of 682 endomyocardial biopsies from 52 grafts in 51 recipients. Acute rejection was diagnosed in 149 biopsies (21.8%). The cumulative 1-year graft survival was 91.5 4%. Four out of seven patients died of irreversible rejection. An univariate analysis using the linearized rate of total rejection showed significantly higher frequency of acute rejection when donor and recipient differed for two HLA-DR antigens compared to zero or one HLA antigen disparity (p less than 0.01), as well as in patients treated with low dose steroids, Cyclosporine (CyA) and Azathioprine (p less than 0.01), compared to treatment with CyA high dose steroids. Other risk factors were graft ischemia extending 60 minutes (p less than 0.05) and patient age exceeding 40 years (p less than 0.05). A multivariate analysis using the competing risk hazard model for irreversible (= lethal) rejection was performed. The presence of two HLA-DR mismatches between donor and recipient was found to be an independent risk factor (relative risk = 8.9), and immunosuppression with CyA and high dose steroids without Azathioprine another (relative risk = 15.3). Potential risk factors such as donor and recipient sex, donor age, prior surgery and time on extracorporeal circulation were not of significant prognostic value neither in regard to rejection nor irreversible rejection.