Although the major histocompatibility complex has been linked with the control and expression of immune response in mammalian species, its importance for heart transplantation has not been demonstrated. The relationship of patient survival to human lymphocyte antigen (HLA) (A and B loci) compatibility was studied in 164 consecutive cyclosporine-treated patients who underwent orthotopic heart transplantation between 1980 and 1986 at Stanford University Medical Center. All patients receiving a transplant within this time frame were included except those for whom HLA typing was unavailable. A mismatched antigen was defined as an antigen present in the donor but not in the recipient. The actuarial four-year survival (Cutler-Ederer) for the 19 patients with 0 or 1 mismatch was 88 +/- 8%; for the 39 patients with 2 mismatches, 70 +/- 12%; for the 73 patients with 3 mismatches, 59 +/- 7%; and for the 33 patients with 4 mismatches, 54 +/- 14%. Both actuarial and linear rate analyses revealed no significant correlation between HLA mismatching and rejection rate, likelihood of death from rejection, or length of time to first episode of rejection. Patients with 3 or 4 mismatches had significantly (p less than 0.05) more infections than those with fewer mismatches. By actuarial analysis, a trend toward a higher number of deaths from rejection and infection was observed in the groups with 3 and 4 mismatches, but it did not achieve statistical significance. The data demonstrate that well-matched HLA grafts are associated with better long-term survival and fewer infections in cardiac transplant patients.