There is strong evidence for a genetic contribution to individual differences in vulnerability to drug addictions. Studies have shown that the 68-base pair repeat polymorphism in the promoter region of the human prodynorphin gene contains a putative AP-1 binding site, and that three or four repeat copies result in greater transcriptional activation. Here, we report on a separate cohort of 302 subjects ascertained and characterized extensively by Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition and Addiction Severity Index criteria as: (1) a control group of 127 subjects with no history of alcohol or drug abuse or dependence; (3) a case group of 82 with cocaine dependence only; and (3) a case group of 93 with cocaine and alcohol codependence. The promoter region of the prodynorphin gene containing the repeat was amplified from genomic DNA by polymerase chain reaction and analyzed via gel electrophoresis. Statistical tests were performed with data stratified by the three major ethnic groups studied: African American, Caucasian and Hispanic. For analyses, genotypes were grouped into short (1,1; 1,2; 2,2), short/long (1,3; 2,3; 1,4; 2,4) and long (3,3; 3,4; 4,4) repeats. Deviation from Hardy-Weinberg Equilibrium in the African American control group necessitated testing for association using grouped genotypes rather than grouped alleles. In controls, a significant difference was found in grouped genotype distribution among ethnicities. We found a point-wise, but not experiment-wise across-ethnicities, significant difference in grouped genotype frequency between the cocaine/alcohol-codependent group and the controls in African Americans, with genotypes containing longer alleles found at higher frequency in the codependent group.