BACKGROUND The benefit of matching donor organs and recipients for HLAs has been well established in renal transplantation and has been suggested for thoracic organ transplantation. To determine the effect of HLA matching in cardiac and single-lung transplantation, the following study was performed. RESULTS Using the joint Thoracic Transplant Registry or the United Network for Organ Sharing and the International Society for Heart and Lung Transplantation, all adult primary heart and single-lung transplant procedures performed in the United States from October 1987 through December 1993 were analyzed to determine the effects of HLA matching on transplant mortality. Both total HLA matches and matches at individual HLA loci were considered. Including HLA matching, 16 potential risk factors for heart transplant outcome and 16 potential risk factors for lung transplant outcome were subjected to multivariate analysis. A total of 10752 heart transplants and 1239 lung transplants were included in the independent analyses for each organ. For heart transplantation, there was a progressive reduction in risk for greater matching (1 or 2 matches: risk ratio, 0.83; 3 matches: risk ratio, 0.67; 4 to 6 matches: risk ratio, 0.59; all P < or = .01). The primary benefit of matching appeared to be at the A and DR loci (risk ratios, 0.87 and 0.79, respectively; P < .001). For lung transplantation, any matching had an independent positive effect on outcome; however, the relationship between numbers of HLA matches and relative risk was not present and ranged from risk ratios of 0.71 to 0.87 (P = .01 and P = .47, respectively). In this analysis, only matching at the A locus appeared to statistically influence outcome (risk ratio, 0.76; P = .01). CONCLUSIONS These data demonstrate that HLA matching independently impacts survival in both heart and single-lung transplantation.