Alleles of the dopamine D2 receptor gene are distinguished by polymorphic A and B TaqI sites approximately 10 kb 3' to the final exon and bordering the second exon, respectively. These alleles have been reported to be more prevalent in heavy substance users than in control populations in several, although not all studies. Meta-analyses of combined data from available work support significant association. Two competing hypotheses could explain this association: (1) the A1 and B1 RFLPs are in linkage disequilibrium with a functional allelic determinant that in some way influences behavior; (2) the affected subjects are drawn disproportionately from populations stratified on the basis of, for example, ethnicity that happen to have higher A1 and B1 RFLP frequencies. We report here data collected from 616 substance-abusing and control individuals that document substantial differences in A1 RFLP frequencies between white and black Americans, the almost exclusive presence of the A3 RFLP in blacks, and low frequencies of rare A4 and B3 RFLPs. In blacks, neither the A1 nor B1 RFLPs display association with substance use, while white individuals display significant association with polysubstance use. When expressed as a percent of the maximum possible disequilibrium, both white and black individuals display strong linkage disequilibrium between these loci, although blacks display many more A1/B2 chromosomes. These racial differences in TaqI RFLP haplotypes underscore the need for caution in interpreting allelic associations when careful matching for ethnicity has not been performed.