Although cigarette smoking is the primary risk factor for non-small cell lung cancer (NSCLC), 25% of cases are not due to smoking or other established risk factors. Chronic lung diseases (chronic bronchitis, emphysema, and asthma) are major sources of inflammation in lung tissue, and a history of these diseases may increase one's risk of NSCLC, especially among never smokers. We used data from the Maryland Lung Cancer Study to investigate whether a history of chronic lung disease is associated with NSCLC risk, and if use of aspirin and/or other non-steroidal anti-inflammatory drugs (NSAIDs) decreases such risk, independently of smoking status. In the present case-control study, 1,660 NSCLC cases and 1,959 population controls were interviewed using a standardized questionnaire. Logistic regression estimated adjusted odds ratios (OR) for having NSCLC by: 1) history and 2) mean duration of chronic lung disease; and 3) regular use, 4) mean frequency, and 5) mean duration of aspirin and/or other NSAIDs. A history of chronic lung disease was statistically significantly associated with having NSCLC (OR = 1.87, 95% confidence interval (CI) 1.54-2.28). When stratified by smoking status, a history of chronic lung disease significantly increased the odds of having NSCLC in never (OR = 1.99, 95% CI 1.19-3.34), former (OR = 1.68, 95% CI 1.29-2.20), and current smokers (OR = 2.40, 95% CI 1.62-3.57), compared to those without chronic lung disease. Regular aspirin use was significantly associated with a 36% decreased risk of NSCLC, compared to non-regular use (OR = 0.64, 95% CI 0.52-0.79), but this association remained significant only in former (OR = 0.62, 95% CI 0.47-0.82) and current smokers (OR = 0.55, 95% CI 0.37-0.81). Regular use of other NSAIDs was associated with a statistically significant increase in the risk of having NSCLC compared to non-regular use (OR = 1.55, 95% CI 1.08-2.22); this association remained significant in former smokers (OR = 1.89, 95% CI 1.12-3.21). This study provides support for: 1) chronic inflammation as a potential contributing factor to NSCLC risk, regardless of smoking status, sex, and race; and 2) regular use of aspirin as a protective factor in former and current smokers.