HLA polymorphism varies among different racial origins. Certain antigens are restricted to a particular ethnic group, suggesting that genetic events might have generated further unique polymorphism following racial diversification. In this study, we have identified and characterized a novel HLA-A allele, officially designated A*8001. The class I molecule, HLA-AXBG, encoded by this allele could not be defined by commonly available HLA antisera. We have identified two alloantisera that appear to be monospecific for this new antigen. The observed frequency of AXBG antigen specificity is 2% in African Americans among the total of 254 tested, but it has not been found in 305 Caucasians tested. IEF and cDNA sequencing analyses on multiple individuals revealed that AXBG antigen defined by the two antisera are encoded by an identical HLA-A*8001 allele and it has a number of unique amino acid residues that have not been observed among other HLA-A alleles but are known to occur in certain human nonclassic class I genes and nonhuman primate class I genes. The ability to identify the new HLA-AXBG antigen will improve the precision of HLA-A typing in black populations and enable us to match a patient with a donor for this otherwise undefined antigen in transplantation.