Background: Activation of TLR3 receptors, which are sensitive to viral infection, has emerged as a possible mechanism that increases alcohol intake in rodents.Objectives: These studies examined whether a history of ethanol dependence exacerbated the increase in drinking driven by the TLR3 agonist poly I:C.Methods: Male C57BL/6J mice (>10 per group) were given access to ethanol (20% v/v) 2 hours a day following a history of home cage drinking or after having been rendered ethanol-dependent using a chronic intermittent ethanol (CIE) vapor model. After testing multiple doses, a 5 mg/kg repeated poly I:C challenge was used to probe the effects of repeated immune challenge, alone or in conjunction with repeated cycles of CIE, on voluntary drinking. An ethanol (12% v/v) operant self-administration model was used to test the effects of poly I:C on stress-induced reinstatement of ethanol seeking and consumption.Results: Poly I:C in naive animals resulted in transient, modest increases in ethanol intake in the home cage and in self-administration (p < 0.05). However, poly I:C challenge resulted in sensitized stress-induced ethanol consumption and evoked a strong and persistent escalation of drinking in mice with a history of dependence (p < 0.05 for both).Conclusion: Activation of viral immune defense may affect ethanol consumption in dependence and sensitivity to future stressors. As patients who suffer from alcohol use disorder are at a heightened risk for viral infection, this interaction could generate risk factors for exacerbating behaviors associated with Alcohol Use Disorders via an immune mechanism.