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Kidney transplants from unrelated live donors have been reported to perform exceedingly well despite poor HLA compatibility. These results were extrapolated to indicate that HLA matching in cadaver kidney transplantation is superfluous provided the ischemic preservation time is kept very short.The influence of HLA matching on the outcome of 2281 transplants from unrelated live donors from 1986 to 1995 was analyzed at 198 transplant centers.The 5-year transplant success rate was significantly associated with the number of HLA-A, -B, and -DR mismatches(P<0.0001). There was a significant on graft survival of mismatches at the class I HLA-A, and -B loci(P=0.001) as well as at the class II HLA-DR locus(P=0.005). In transplants from both spouses and nonspouses, cases with no HLA-DR mismatch were found more often than would be expected if transplant donors were selected by chance, which indicates that efforts of prospective HLA matching had been made.The outcome of kidney transplants from unrelated live donors is strongly influenced by HLA compatibility. Short exposure of donor kidneys to ischemia does not eliminate the influence of HLA matching on graft survival.