Possible association between polymorphisms at the D2 dopamine receptor gene (DRD2) and alcohol dependence has been controversial since first proposed in 1990. The most studied polymorphisms to date are the TaqI "A" and "B" systems; they are unlikely to convey a physiological effect directly, and have not been demonstrated to be in linkage disequilibrium with any common polymorphism more likely to convey such an effect, in populations of European ancestry. A recently-described polymorphism in the promoter region of the DRD2 gene with possible effects on gene regulation is the first functional polymorphism described at this locus frequent enough in European-Americans (EAs) to have the potential to explain the positive findings. The goals of this study were to determine if we could replicate any previously reported associations particularly with the "A" and "B" systems and alcohol dependence or severity of alcohol dependence, using a screened control group design. We also studied the promoter system, "D" system, and 3 locus haplotypes. To test the hypothesis of an association rigorously, we studied four DRD2 polymorphic systems in 160 EA alcohol dependent subjects and 136 screened EA control subjects. To increase our potential to detect association with other polymorphisms at the locus, we also constructed 3 locus haplotypes including the DRD2 "A," "D," and promoter systems in both samples. There were no significant differences in allele frequencies between alcohol dependent and screened control subjects for any of the four systems studied. There were also no differences in 3-locus haplotype frequencies between these groups. Analysis based on severity of alcohol dependence also yielded no significant association. The screened control allele frequencies did not differ from allele frequencies we reported previously in unscreened controls. Thus, we replicated previous findings of no association between DRD2 alleles and alcohol dependence. These results can now be extended to include haplotypes containing the possibly-functional promoter system polymorphism. Explanations previously offered to explain lack of association (regarding alcohol dependence severity, and use of screened vs. unscreened controls) were not validated. These results are consistent with no effect of DRD2 polymorphisms on behavioral phenotypes related to alcohol dependence.