The heavy chain of platelet glycoprotein Ib (GPIb) contains two prevalent sequence polymorphisms. The first, Thr/Met 145 is responsible for the human platelet alloantigen system, human platelet antigen (HPA)-2. The second is a tandem repeat polymorphism that consists of four variants, A, B, C, and D. Previous linkage studies in Caucasian and Eastern Asian populations have demonstrated that HPA-2a (Thr 145 ) is associated with variants C and D, while HPA-2b (Met 145 ) is associated with variants A and B. We have determined HPA-2 and variable number of tandem repeats (VNTR) genotypes in three different North American ethnic groups. The gene frequency of HPA-2b in the North American Indians was intermediate between African Americans and Caucasians, and similar to the frequency previously reported in Japanese. Furthermore, the VNTR-A allele, which previously has been reported only in Eastern Asian populations, was present in two of 101 North American Indian individuals. These data are consistent with the hypothesis that the first Native Americans migrated to North America from Eastern Asia. Analysis of HPA-2 and VNTR haplotypes demonstrated an unexpected linkage pattern in the African American population. A rare GPIb␣ isoform, HPA-2b/VNTR-C, was present in 2.2% of African American haplotypes. Furthermore, a novel GPIb␣ isoform, HPA-2a/VNTR-B, was present in 6.5% of African American haplotypes. These data suggest a more complex evolutionary pattern of GPIb␣ isoforms than previously proposed. Am.