HLA-DRB1, -DQB1 and -DPB1 polymorphisms were investigated in two African populations, the Basse Lobaye Aka Pygmies of the Central African Republic, and a Bantu-speaking group from the Democratic Republic of Congo Kinshasa. Allelic and haplotypic frequency distributions reveal marked differences between the two populations in spite of their geographical proximity: the Aka exhibit high frequencies for several alleles, especially at the DPB1 locus (0.695 for DPB1*0402), probably due to rapid genetic drift, while the Bantu distributions are more even. Genetic distances computed from DRB1 allelic frequencies among 21 populations from North and sub-Saharan Africa were applied to a multidimensional scaling analysis. African populations genetic structure is significantly shaped by linguistic differentiation, as confirmed by an analysis of molecular variance. However, selective neutrality tests indicate that many African populations exhibit an excess of heterozygotes for DRB1, which is likely to explain the genetic similarity observed between some North African and Bantu populations. Overall, this study shows that natural selection must be taken into account when interpreting the patterns of HLA diversity, but that this effect is probably minor in relation to the stochastic events of human population differentiations.