In this study, we examined whether IL-18 plays a role in lung inflammation following alcohol (EtOH) and burn injury. Male rats (~250 g) were gavaged with EtOH to achieve a blood EtOH level of ~100 mg/dL prior to burn or sham injury (25% TBSA). Immediately after injury, rats were treated with vehicle, caspase-1 inhibitor AC-YVAD-CHO to block IL-18 production or with IL-18 neutralizing anti-IL-18 antibodies. In another group, rats were treated with anti-neutrophil anti-serum ~16 h before injury to deplete neutrophils. On day one after injury, lung tissue IL-18, neutrophil chemokines (CINC-1/CINC-3), ICAM-1, neutrophil infiltration, myeloperoxidase (MPO) activity, and water content (i.e. edema) were significantly increased in rats receiving a combined insult of EtOH and burn injury compared to rats receiving either EtOH intoxication or burn injury alone. Treatment of rats with caspase-1 inhibitor prevented the increase in lung tissue IL-18, CINC-1, CINC-3, ICAM-1, MPO activity and edema following EtOH and burn injury. The increase in lung IL-18, MPO, and edema was also prevented in rats treated with anti-IL-18 antibodies. Furthermore, administration of anti-neutrophil anti-serum also attenuated the increase in lung MPO activity and edema, but did not prevent the increase in IL-18 levels following EtOH and burn injury. These findings suggest that acute EtOH intoxication before burn injury upregulates IL-18 which in turn contribute to increase neutrophil infiltration. Furthermore the presence of neutrophils appears to be critical for IL-18-meditaed increase lung tissue edema following a combined insult of EtOH and burn injury.