The HLA class I and II phenotypes of the three population groups in the Cape Province of South Africa were determined. The HLA-A,B, and C antigens were tested in 1027 South African Negroes (Xhosa), 3716 Cape Coloureds and 1059 South African Caucasoids. This is the first study which has also included the class II antigens in the Southern African Negroes (Xhosa). The numbers tested for the DR and DQ antigens were smaller, as only typings done after the 8th Histocompatibility Workshop were included. A comparison was made between the frequencies in the Xhosa, the Cape Coloureds and the South African Caucasoids as well as the Nigerians, another group who also belong to the Bantu-speaking division of African Negroes and who were recently studied. The antigen, gene and haplotype frequencies were estimated in all three groups, and the genetic distances calculated. Striking differences in gene and haplotype frequencies between the various populations were seen. For example, Bw42 had a phenotype frequency of 0.062 in the Cape Coloureds, 0.213 in the Xhosa and 0.004 in the South African Caucasoids. The Xhosa showed marked differences in HLA distribution compared to the other Negro group (Nigerians), which can be attributed to a Khoisan admixture, e.g. HLA-DR4 had a phenotype frequency of 0.134 in the Xhosa and only 0.010 in the Nigerians. The haplotype B8,DR3, seen in association with many autoimmune diseases, had a significant delta value in all three populations.