Rationale: Previous studies have linked the development and severity of acute respiratory distress syndrome with a history of alcohol abuse. In clinical studies, this association has been centered upon depletion of pulmonary glutathione and subsequent chronic oxidant stress. Objective: The impact on redox potential of the plasma or pulmonary pools, however, has never been reported. Method: Plasma and bronchoalveolar lavage fluid were collected from otherwise healthy alcohol dependent subjects and controls matched by age, gender, and smoking history. Measurements: Redox potential was calculated from measured reduced and oxidized glutathione in plasma and lavage. Main Results: Among either nonsmoker or smoker subjects, lavage fluid glutathione redox potential was more oxidized in alcohol abusers by ~ 40 mV which was not altered by dilution. This oxidation of the airway lining fluid associated with chronic alcohol abuse was independent of smoking history. A shift by 20 mV in plasma glutathione redox potential, however, was noted only in subjects who both abused alcohol and smoked. Conclusion: Chronic alcoholism was associated with alveolar oxidation and with smoking, systemic oxidation. However, systemic oxidation did not accurately reflect the dramatic alcohol-induced oxidant stress in the alveolar space. While there was compensation for the oxidant stress caused by smoking in control groups, the capacity to maintain a reduced environment in the alveolar space was overwhelmed in those who abused alcohol. The significant alcohol-induced chronic oxidant stress in the alveolar space and the subsequent ramifications may be an important modulator of the increased incidence and severity of ARDS in this vulnerable population.