Increased physical activity has been associated with decreased lung cancer risk. However, no previous investigation has examined physical activity in relation to lung cancer histologic types by smoking status. The authors investigated these relations in the National Institutes of Health-AARP Diet and Health Study among 501,148 men and women aged 50-71 years at baseline in 1995-1996. During follow-up to 2003, 6,745 lung carcinomas occurred (14.8% small cell, 40.3% adenocarcinoma, 19.7% squamous cell, 6.1% undifferentiated large cell, 7.2% non-small cell not otherwise specified, and 11.8% carcinoma not otherwise specified). Among former smokers, the multivariate relative risks of small cell, adenocarcinoma, squamous cell, and undifferentiated large cell carcinomas comparing the highest with the lowest activity level (> or =5 times/week vs. inactive) were 0.93 (95% confidence interval (CI): 0.67, 1.28), 0.79 (95% CI: 0.67, 0.94), 0.73 (95% CI: 0.57, 0.93), and 0.61 (95% CI: 0.38, 0.98), respectively. Among current smokers, corresponding values were 0.77 (95% CI: 0.58, 1.02), 0.76 (95% CI: 0.61, 0.95), 0.85 (95% CI: 0.65, 1.11), and 1.10 (95% CI: 0.69, 1.78). In contrast, physical activity was unrelated to lung carcinoma among never smokers (P(interaction) between physical activity and smoking for total lung carcinomas = 0.002). The inverse findings among former and current smokers in combination with the null results for physical activity among never smokers may point toward residual confounding by cigarette smoking as an explanation for the relations observed.