Evidence from genetically modified mice suggests a role for NPY in regulation of ethanol intake, but results of pharmacological studies have been more variable. We have previously shown that potentiation of NPY signaling through antagonism at NPY-Y2 receptors decreases operant responding for ethanol in Wistar rats without a history of dependence. Here, we examined the effects of Y2-antagonism in animals with a history of dependence induced by long-term intermittent exposure to ethanol vapor. The Y2-receptor antagonist BIIE0246 suppressed operant responding for ethanol (approximately 50%, p=0.01), at a dose (0.5 nmol i.c.v.) which was ineffective in subjects without a history of dependence. Responding for the ethanol-free control solution was unaffected. These data confirm that antagonism at central NPY-Y2 receptors selectively suppresses motivation to self-administer ethanol, and indicate that the NPY system is sensitized in animals with a history of dependence. This may render the NPY system, and Y2 receptors in particular, an attractive target for treatment of alcohol dependence.