A single base deletion in HLA-G (1597DeltaC) that is a null allele for the full-length protein is found at frequencies of 6%-11% in populations of African descent. To test the null hypothesis that 1597DeltaC "drifted" to this frequency by neutral evolutionary processes, we compared the pattern of variation and linkage disequilibrium (LD) around this allele and around a conservative amino acid replacement polymorphism in HLA-G (T31S) in African-Americans and Nigerians. There was no significant LD between the 31S allele and flanking STRPs at 150-200 kb in either sample, but significant LD was observed between the 1597DeltaC allele and the same flanking STRPs (p < 0.001 in both samples). To further characterize the evolutionary history of these variants, age estimates were determined assuming evolutionary neutrality. If these alleles were neutral, their frequencies indicate that they arose approximately 9500 (95% CI = 1557, 17557) generations ago (200,000 years). However, using LD to estimate the allele age, the 1597DeltaC allele was estimated to have arisen only 744 (95% CI = 375,2713) generations ago (18,000 years ago), whereas the 31S allele has a much older estimate of 3241 (95% CI = 1680, 20500) generations ago (81,000 years ago). These data suggest that these two polymorphisms in the HLA-G gene have had different evolutionary histories. We propose that natural selection has acted on the 1597DeltaC allele.