The HLA-A, -B, and -C antigens of 290 and the DR antigens of 212 !Kung San individuals were characterized. The most frequent antigens were HLA-A30 gene frequency ( gf) = 0.193, Bw58 ( gf = 0.303), Cw6 ( gf = 0.327), DR4 ( gf = 0.273), and DQw3 ( gf = 0.553). An unexpected finding was the low frequency of the classic African black antigen Bw42 ( gf = 0.004). Marked differences as well as similarities in HLA gene frequencies were observed between the San and the South African Negroes, supporting the view that they had a common origin and were then separated for a very long time. During this period differences developed as a result of selective advantage in the Negroes following the pastoralist-agriculturalist way of life as opposed to the hunter-gatherer way of life. The picture is further complicated by the fact that gene flow, mostly from the San to the southern African Negroes, took place when they met again a few hundred years ago. The data also illustrate HLA haplotypes, linkage disequilibria, and four-locus haplotypes not previously seen in other human populations. The most frequent four-locus haplotype in the San, HLA-Aw43, Cw7, B7, DRw6 was also different from A30, Cw2, Bw42, DR3, the most common among the South African Negroes.