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Varenicline, a pharmacotherapy for tobacco addiction, reduces alcohol consumption in humans and rodents. The therapeutic potential of varenicline would escalate if it also diminished conditioned responses elicited by alcohol-predictive cues, which can precipitate relapse in abstinent individuals. We investigated this application, along with the underlying neural substrates, using a robust preclinical assay in which relapse to alcohol-seeking was triggered by re-exposure to an alcohol-associated environmental context. Male, Long-Evans rats received Pavlovian conditioning sessions in which one auditory conditioned stimulus (CS+) was paired with 15% ethanol and a second conditioned stimulus (CS−) was not. Ethanol was delivered into a port for oral consumption and port entries triggered by each CS were recorded. Extinction was then conducted in a different context where the CS+ and CS− were presented without ethanol. To stimulate relapse, both cues were subsequently presented without ethanol in the prior conditioning context. Systemic varenicline (0, 0.5 or 2.5 mg/kg; intraperitoneal) blocked context-induced relapse to alcohol-seeking without affecting the ability to make a port entry. It also reduced context-induced relapse to sucrose-seeking, but only at the 2.5 mg/kg dose. Neuropharmacological studies showed that context-induced relapse to alcohol-seeking was attenuated by bilateral microinfusion of varenicline (0.3 μl/side) into the nucleus accumbens (NAc; 0 or 3.5 μg), but not the ventral tegmental area (0, 2 or 4 μg). These data show for the first time that varenicline reduces relapse triggered by contexts that predict alcohol, and suggest that nicotinic acetylcholine receptors in the NAc are critical for this effect.