Review of 448 cyclosporine-treated heart transplant recipients was undertaken to examine the relationship of donor-recipient HLA compatibility to patient survival, rejection, and death from coronary artery disease (CAD). Pre-Tx crossmatching and panel-reactive antibody (PRA) were correlated to survival as well. Overall patient survivals were 78%, 70%, and 65% at 1, 3, and 5 years post-Tx, respectively. Matching of donor-recipient HLA did not improve outcome in that 1, 3, and 5 year survivals for well-matched (≤2 A, B, or 0–1DR mismatches [MMs]) vs. poorly matched (>2 A, B, or 2 DR MMs) recipients were comparable and not significantly different. Well-matched recipients, however, experienced significantly fewer rejections (1.06±1.2 vs. 1.96±1.0, P2A, B MMs and 1.1±0.9 vs. 2.0±1.1 for 0–1 DR MMs vs. 2 DR MMs, P<0.01). Moreover, HLA-DR, but not HLA A, B, was a significant (P<0.01) predictor of early rejection (<30 days) in that 65% (165/254) of poorly matched vs. only 40% (95/194) of well-matched HLA-DR recipients experienced early rejections. Interestingly, an inverse relationship was found between HLA A and B MM, but not HLA-DR MM, and death from coronary artery disease in that 17% (19/111) of well-matched vs. 9% (32/327) of poorly matched patients died from CAD. Pre-Tx PRA did not impact patient survival or rejection. Donor-recipient crossmatching was performed utilizing the NIH and/or antiglobulin (AHG) procedures. No survival differences were observed at 1, 2, and 3 years post-Tx when comparing outcome for the 24 NIH cross-match (XM)-positive (+) with the 424 NIH-XM-nega-tive patients. Only 10 patients (10/125 AHG-tested recipients) displayed a positive AHG recipient antidonor reactivity. When these 10 AHG-XM (+) sera were treated with dithioerythritol (to inactivate IgM) all 10 converted to a negative reactivity, indicating that a positive crossmatch due to IgM reactivity should not be considered a contraindication to cardiac transplantation. These data also suggest that the reactivity of the 24 NLH-XM(+) sera were most likely due to IgM, and that poorly matched heart recipients may benefit from a more aggressive immunosuppressive regimen to prevent early rejections.