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ABSTRACT. Objective: The effects of alcohol (ethanol) are well documented and contribute to signifi cant health problems and fi nancial burden on the health care system. Several mouse models have been described that facilitate studies of the effects of alcohol on the mouse immune system. Our goal was to establish a chronic alcohol mouse model using the immunodefi cient NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mouse. This severely immunodefi cient model has previously been shown to allow effi cient engraftment of human hematopoietic repopulating cells and cancer cells, thereby facilitating diverse studies on human hematopoiesis, immune cell function, and oncogenesis in vivo. Method: NSG mice were provided ethanol in their drinking water as the only available fl uid, starting at 5% weight/volume (w/v) and subsequently were increased to 10%, 15%, and 20% w/v. Mice were then maintained at 20% w/v, a level that models chronic alcohol use in humans. Alcohol consumption and weight were monitored. Results: NSG mice readily consumed alcohol throughout the study and showed no adverse effects. No signifi cant difference between group mean weights was identifi ed the day before increasing the ethanol dose or at the end of 5 weeks at 20% w/v (p > .28). While the mice were maintained at 20% w/v ethanol, the mean daily ethanol intake was 27.2 g/kg of body weight, 32% of caloric intake. Conclusions: Here we have established a chronic alcohol mouse model using the powerful immunodefi cient NSG mouse. This model should allow for novel studies on the effects of alcohol on engrafted human cells, including studies on the effects of alcohol on hematopoiesis, immunity, and cancer. (J. Stud. Alcohol Drugs, 73, 933-937, 2012)