The mu opioid receptor is implicated in the reward, tolerance and withdrawal effects of alcohol and other drugs of abuse. This hypothesis is supported by the effects of alcohol on beta-endorphin release, of mu opioid receptor agonists and antagonists on alcohol consumption, and by the activation of the dopaminergic reward system by both alcohol and opiates. In addition, the murine mu opioid receptor locus, Oprm, is implicated as the major quantitative trait locus (QTL) affecting the different levels of morphine consumption between two inbred mouse strains that also exhibit differences in alcohol and cocaine consumption. Detection of genetic variation affecting OPRM1 expression or mu opioid receptor function would be an important step towards understanding the origins of inter-individual variation in response to mu opioid receptor ligands and in diseases of substance dependence. We directly sequenced the human mu opioid receptor locus, OPRM1, to detect natural variation that might affect function and/or be associated with psychiatric phenotypes related to opioid function. Four DNA sequence variants were found: three non-synonymous substitutions (Ala6Val [rare], Asn40Asp, [0.10-0.16], Ser147Cys [rare]) and one intronic variant (IVS2+691G/C [0.55-0.63]). OPRM1 alleles, genotypes and haplotypes from three psychiatrically characterized population samples (US Caucasian [USC, n=100], Finnish Caucasian [FC, n=324] and Southwestern American Indian [SAI, n=367]), were used to perform association and sib-pair linkage analyses with alcohol and drug dependence diagnoses. No significant association of OPRM1 genetic variation to phenotype was observed. This analysis has 80% power to detect a small to moderate effect of OPRM1 variation on alcohol dependence and 100% power to detect effects of the magnitude of the ALDH2*2 variant. While these data do not support a role of the mu opioid receptor in susceptibility to alcohol dependence, the potential relationship between OPRM1 genetic variation and response to endogenous opioids and exogenous opiates can now be investigated.