Variation at the UDP-glucuronosyltransferase (UGT) 1A1 gene promoter is present in humans. Variable numbers of TA repeats in the TATA box of this gene are found which are inversely related to levels of gene expression. We investigated this polymorphism in 658 individuals from a worldwide sample of 15 aboriginal and two admixed human populations. This study shows that there is a great deal of variability across ethnic groups with regard to UGT1A1 allele frequencies, with the most common allele varying in frequency from 33% to 91%. Populations of African origin harbor four different alleles while non-African populations appear to have only two alleles. In addition, alleles associated with lower gene expression levels reach the highest frequencies in populations of African origin and lowest among Asians and Amerindians. Thus, more variability in the metabolism of drugs eliminated by UGT1A1 glucuronidation should be expected in populations of Sub-Saharan African origin. The sequence analysis of nine primate species shows that the number of TA repeats has increased during primate evolution achieving the largest number in humans. We suggest that the UGT1A1 promoter variability does not reflect historical relationships between populations and that it may be maintained by natural selection. Our findings are consistent with the proposal that the TA repeat variation is a balanced polymorphism.