Reactive oxygen species (ROS) are important in the initiation and promotion of cells to neoplastic growth. In this context, cigarette smoke exposure, the primary risk factor in lung cancer development, leads to high levels of ROS within the human airway. Although well-equipped with an integrated antioxidant defense system consisting of low-molecular weight antioxidants such as glutathione and intracellular enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase, the lungs are vulnerable to increased endogenous and exogenous oxidative insults. Antioxidants increase in response to oxidative stress and minimize ROS-induced injury in experimental systems, indicating that antioxidant levels may determine whether ROS can initiate lung carcinogenesis. On this basis, we hypothesized that antioxidants would be decreased in lung carcinoma cells as compared with tumor-free adjacent lung tissues. Antioxidant expression was evaluated in 16 lung tumor and 21 tumor-free lung tissues collected between the years 1993 and 2001 from 24 individuals with surgically resectable non-small cell lung cancer, i.e., adenocarcinoma and squamous cell carcinoma. Total SOD activity was increased (P = 0.035), catalase activity decreased (P = 0.002), and glutathione and glutathione peroxidase were similar in tumors compared with tumor-free lung tissues. Alterations in antioxidant activities were attributable to increased manganese SOD and decreased catalase protein and mRNA expression in tumors. Immunohistochemical localization of catalase in the lung revealed decreased or no expression in the tumor cells, although healthy adjacent airway epithelial cells were strongly positive for catalase. Parallel changes in antioxidant activities, protein, and mRNA expression were noted in A549 lung carcinoma cell lines exposed to cytokines (tumor necrosis factor-alpha, interleukin 1beta, and IFN-gamma). Thus, inflammation in the lung may contribute to high levels of manganese SOD and decreased catalase, which together may lead to increased hydrogen peroxide intracellularly and create an intracellular environment favorable to DNA damage and the promotion of cancer.