Abstract:  The effect of catechol-O-methyltransferase (Comt) gene disruption on the voluntary oral consumption of water, ethanol (2.5–20%, v/v) and cocaine (0.1–0.8 mg/ml) was studied in the free-choice, two-bottle paradigm in male and female mice. Solutions containing ethanol or cocaine, or tap water were available ad libitum from drinking burettes for 4 weeks. Catechol-O-methyltransferase-deficient male mice consumed significantly more ethanol than their wild-type male littermates. In contrast, female mice did not show genotype differences in the consumption of ethanol solutions. During the cocaine experiment, male mice developed either a side preference or an aversion that obscured cocaine consumption. This pattern of drinking was not dependent on Comt genotype. In female mice, Comt genotype was not associated with cocaine consumption. In conclusion, disruption of Comt gene influenced ethanol consumption in a gender-dependent manner in mice, supporting the hypothesis that low catechol-O-methyltransferase activity is one of the predisposing factors for high alcohol consumption in males.