AbstractOpioid receptors and their endogenous peptide ligands play important roles in neurotransmission and neuromodulation in response to addictive drugs such as heroin, cocaine, and alcohol. In an earlier study, we reported that variation in the genes encoding the κ‐opioid receptor (OPRK1)and its peptide ligand (PDYN)were associated with the risk for alcoholism. We continued our investigation of the role of the opioid system in alcohol dependence by analyzing the genes encoding the µ‐ and δ‐opioid receptors and their peptide ligands. We analyzed 18OPRM1SNPs, 18OPRD1SNPs, 7PENKSNPs, and 7POMCSNPs in a sample of 1923 European Americans from 219 multiplex alcohol dependent families. Employing a family‐based test of association, we found no evidence that these four genes were significantly associated with alcohol dependence. We also did not find association between these genes and illicit drug dependence. Secondary analyses employing the narrower phenotype of opioid dependence (83 affected individuals) demonstrated association with SNPs inPENKandPOMC, but not inOPRM1orOPRD1. Haplotype analyses provided further support for the association ofPENKandPOMCwith opioid dependence. Therefore, our data provide no support for the idea that variations inOPRM1,OPRD1,PENKandPOMCare associated with alcohol dependence or general illicit drug dependence, but variations inPENKandPOMCappear to be associated with the narrower phenotype of opioid dependence in these families. © 2007 Wiley‐Liss, Inc.