We conducted a case control study of selective cyclooxygenase-2 (COX-2) blocking agents and lung cancer. A total of 492 newly diagnosed lung cancer cases were ascertained during January 1, 2002 to September 30, 2004, at The Ohio State University Medical Center, Columbus, Ohio. All cases were confirmed by examination of the pathology report. Healthy population controls without cancer were ascertained during the same time period. Controls were frequency matched at a rate of 2:1 to the cases by age, gender, and county of residence. We collected information on type, frequency, and duration of use of selective COX-2 inhibitors (primarily celecoxib or rofecoxib) and nonselective NSAIDs such as ibuprofen and aspirin. Estimates of odds ratios (OR) were obtained with adjustment for cigarette smoking, age and other potential confounders using logistic regression analysis. Odds Ratios for selective COX-2 inhibitors were adjusted for past use of other NSAIDs. Use of any selective COX-2 inhibitor for more than one year produced a significant (60%) reduction in the risk of lung cancer (OR=0.40, 95% CI=0.19-0.81). Observed risk reductions were consistent for men (OR=0.26, 95% CI=0.10-0.62) and women (OR=0.52, 95% CI=0.24-1.13) and for individual COX-2 inhibitors (OR=0.28, 95% CI=-0.12-0.67, for celecoxib and OR=0.55, 95% CI=0.19-1.56, for rofecoxib). Intake of ibuprofen or aspirin also produced significant risk reductions (OR=0.40, 95% CI=0.23-0.73 and OR=0.53, 95% CI=0.34-0.82, respectively), whereas acetaminophen, an analgesic with negligible COX-2 activity, had no effect on the risk (OR=1.36, 95% CI=0.53-3.37). This investigation demonstrates for the first time that selective COX-2 blocking agents have strong potential for the chemoprevention of human lung cancer.