Alpha-globin gene cluster haplotypes were determined in Southern African San and negroid populations. Significant differences (P less than .01) between the two groups were found at three of the nine loci in the cluster. The most striking difference, however, was the relatively low level of variation found in the San (alpha alpha)-associated haplotypes and the high level in the SA blacks. This trend was also observed for the 3' hyper-variable region. Nineteen different haplotypes were identified among the 36 haplotypes studied in the black population, but only seven different ones were found among the 37 haplotypes in the San; five were common to both populations. The common San haplotype, (+--MPZ+---), had a frequency of .57 in the San and .11 in the black population; the common SA black haplotype, (---MZ----), occurred at a frequency of .17 but was absent in the San. In the SA black population significant linkage disequilibrium is present between five of the RFLP loci, including the extreme 5' and 3' markers, confirming the absence of a recombination hot spot in the alpha-globin gene cluster.