We sought to determine whether variants of the human alpha-1-antitrypsin (AAT) gene, also known as "PI," or "SERPINA1," are associated with human immunodeficiency virus (HIV) infection in 2 African-based populations from HIV-pandemic sub-Saharan Africa. Eleven commonly occurring African-associated polymorphic markers in the coding and intronic regions of the AAT gene were analyzed via denaturing gradient gel electrophoresis. A significant association between HIV-1 infection and the presence of an allelic variant was observed in the case of the M2 and A332A haplotypes, thus presenting AAT as a potentially novel HIV-1 susceptibility locus.