In an analysis of over 4000 cyclosporine-treated recipients of second kidney transplants we observed a strong effect of HLA matching in living-related and cadaver transplants. In contrast to the results obtained in first cadaver transplants, second cadaver transplants benefited substantially from matching for HLA-A locus antigens. The strongest effect of matching was found when HLA-A, HLA-B, and HLA-DR antigens were analyzed together: 214 second grafts with no mismatch had a survival rate of 82 ± 3% at two years in contrast to a 49 ± 4% rate in 149 grafts with 6 mismatches (P<0.0001, log rank). Patients whose first graft functioned for more than 1 year had a significantly higher second graft survival rate than patients with shorter first graft duration. Because the effect of HLA matching is particularly strong in patients with <1 year first graft duration, it is suggested that HLA well-matched kidneys should be allocated to them with priority.