Alcohol and nicotine are among the top causes of preventable death in the United States. Unfortunately, people who are dependent on alcohol are more likely to smoke than individuals in the general population. Similarly, smokers are more likely to abuse alcohol. Alcohol and nicotine codependence affects health in many ways and leads to poorer treatment outcomes in subjects who want to quit. This study examined the interaction of alcohol and nicotine during withdrawal and compared abstinence symptoms during withdrawal from one of the two drugs only vs both. Our results indicate that simultaneous withdrawal from alcohol and nicotine produces physical symptoms that are more severe and last longer than those experienced during withdrawal from one of the two drugs alone. In animals experiencing withdrawal after chronic ethanol treatment, acute nicotine exposure was sufficient to prevent abstinence symptoms. Similarly, symptoms were prevented when alcohol was injected acutely in mice undergoing nicotine withdrawal. These experiments provide evidence for the involvement of the nicotinic cholinergic system in alcohol withdrawal. Furthermore, the outcomes of intracranial microinfusions of mecamylamine, a nonselective nicotinic receptor antagonist, highlight a major role for the nicotinic receptors expressed in medial habenula and interpeduncular nucleus during withdrawal. Overall, the data support the notion that modulating the nicotinic cholinergic system might help to maintain long-term abstinence from alcohol.