Background: The neurobiology of alcohol dependence (AD) involves alterations in neurotransmitters and the stress response. We hypothesized that an interaction between functional variants of dopaminergic and neurotrophic genes may influence drinking in AD. Methods: The relationship between alcohol consumption and single-nucleotide polymorphisms, Val66Met in the brain-derived neurotrophic factor (BDNF), and Val158Met in the catechol-O-methyltransferase (COMT), was analyzed among 281 alcohol-dependent individuals. Results: Individuals carrying both the COMT Met158Met genotype and the BDNF Val66Val genotype drank more than those with other variants of these genes (P = 0.039). Those who had a family history of AD also drank more than those without a family history (P = 0.048). Patients with both Met/Met genotype in the COMT Val158Met polymorphism and Val/Val genotype in the BDNF Val66Met polymorphism suffered from more health problems than those carrying other variants (P = 0.030) and had lower motivation to change drinking patterns (P = 0.031). Conclusions: Patients carrying both the BDNF Val66Val and COMT Met158Met variants had higher alcohol consumption. These effects may be influenced by the effects of BDNF and COMT on dopamine responses to alcohol. Motivation-enhancing strategies might benefit the group of patients identified by genotyping in this study, and also treatment aimed at reducing alcohol consumption.