We studied the influence of HLA mismatches on T lymphocyte cultures that were derived from endomyocardial biopsies (EMB) from 118 heart transplant recipients. From patients with DR mismatches, the majority of the EMB-derived cultures were dominated by CD4, while in patients without DR mismatches, CD8 was the predominant T cell subset. The majority (75%) of the cultures were cytotoxic against donor antigens. A significantly (P < 0.005) lower proportion of the cultures showed cytotoxicity (36%) against HLA-A antigens when compared to HLA-B (53%) or HLA-DR (49%). A dose effect phenomenon was detected for all HLA antigens, including HLA-A: a higher number of A, B or DR mismatches resulted in a higher number of cytotoxic cultures directed against these antigens. B and DR matching had the greatest influence on 6 month freedom from rejection. Both our experimental and clinical data indicated that HLA matching played a role in the immune response against a transplanted heart.