In the present investigation we hypothesized the A118G (Asn40Asp) polymorphism of the mu-opioid receptor gene (OPRM1) as a particular vulnerability factor for heroin and alcohol dependence. Therefore, we tested this hypothesis in two independent large samples by two different methods: a case-control sample (comprising n = 287 heroin and n = 221 alcohol study subjects versus n = 365 nondependent controls) and a family-controlled sample of 111 parent-offspring trios of heroin-dependent study subjects and 75 parent-offspring trios of alcohol-dependent study subjects to avoid stratification artifacts. In both patient samples and by both methods we were unable to corroborate the hypothesis of OPRM1 A118G polymorphism as a particular risk factor for any kind of substance dependence including opioid addiction. In addition, there was no significant association between the endophenotype of the individuals under study (e.g., comorbidity, severity of illness) and a particular genotype of OPRM1.