A number of findings showed the similarity among the various substance use disorders (SUD). The heritability of substance dependence (SD) liability is based on polymorphisms at the genes that are likely to be related to the function of the central nervous system and, possibly, the biotransformation of xenobiotics. Associations have been found between the dopamine D5 gene receptor (DRD5) and liability to SD, novelty seeking, and antisocial behavior. This report is a replication of this association in an independent case-control sample. Subjects were participants in a family/high-risk study of SUD in which probands were adult males with or without a DSM-III-R diagnosis of SUD. DNA samples were collected from the members of probands’ nuclear family. The results showed a comparison of the genotypic distributions in the control and SD groups of the replication and original samples. Like the original data, the replication showed a significant over-representation of the modal allele in the affected groups, which confirmed the prior association finding in this new sample. Moreover, the similarity of the results was striking. The data culled from this research and the original study justifies further investigation. Tables, references