Context: Alcohol dependence is a common neuropsychiatric disorder with high heritability. However, genetic association studies on alcohol dependence are often troubled by nonreplication. The use of intermediate phenotypes may help make clear the mode of action of various candidate genes and improve the reproducibility of genetic association studies. Objective: To test central dopamine receptor sensitivity as an intermediate phenotype for alcohol dependence, specifically evaluating the hypothesis that the dopaminergic genes COMT Val158Met and DRD2 Taq1A affect dopamine receptor sensitivity. Design: Case-control pharmacogenetic challenge study. Setting: Patients with alcohol dependence admitted for detoxification were compared with healthy control subjects matched for age and level of education. Participants: Patients (n = 110) were a consecutive sample, whereas controls (n = 99) were recruited through advertisements in regional newspapers. Intervention: A dopamine challenge test was subcutaneously administered using the dopamine agonist apomorphine hydrochloride (0.005 mg/kg). Main Outcome Measures: Outcome measures were plasma growth hormone levels and results of a continuous performance task. Results: Central dopamine receptor sensitivity is reduced in alcohol dependence, and this is modulated by dopaminergic genes. Specifically, DRD2 Taq1A genotype affected dopamine receptor sensitivity as measured by plasma growth hormone levels, and COMT Val158Met genotype affected dopamine receptor sensitivity as measured by performance on a continuous performance task. In a logistic regression analysis, reduced dopamine receptor sensitivity on both measures predicted alcohol dependence, without an additive effect of the COMT Val158Met and DRD2 Taq1A genotypes. Conclusions: COMT Val158Met and DRD2 Taq1A may affect the intermediate phenotype of central dopamine receptor sensitivity. COMT Val158Met and DRD2 Taq1A may confer their risk of alcohol dependence through reduced dopamine receptor sensitivity in the prefrontal cortex and hindbrain, respectively.