We have shown previously that voluntary ethanol consumption and resistance to ethanol-induced sedation are inversely related to neuropeptide Y (NPY) levels in NPY-knock-out (NPY/) and NPY-overexpressing mice. In the present report, we studied knock-out mice completely lacking the NPY Y1 receptor (Y1/) to further characterize the role of the NPY system in ethanol consumption and neurobiological responses to this drug. Here we report that male Y1/mice showed increased consumption of solutions containing 3, 6, and 10%(v/v) ethanol when compared with wild-type (Y1/) control mice. Female Y1/mice showed increased consumption of a 10% ethanol solution. In contrast, Y1/mice showed normal consumption of solutions containing either sucrose or quinine. Relative to Y1/mice, male Y1/mice were found to be less sensitive to the sedative effects of 3.5 and 4.0 gm/kg ethanol as measured by more rapid recovery from ethanol-induced sleep, although plasma ethanol levels did not differ significantly between the genotypes. Finally, male Y1/mice showed normal ethanol-induced ataxia on the rotarod test after administration of a 2.5 gm/kg dose. These data suggest that the NPY Y1 receptor regulates voluntary ethanol consumption and some of the intoxicating effects caused by administration of ethanol.