Abstract Background: Moderate and vigorous physical activity have shown inverse associations with lung cancer (LC) risk, as well as a dose-response effect, in previous studies. One mechanism for this occurrence is the anti-inflammatory effect of physical activity, which may occur due to a reduction in visceral fat mass, with a decreased production and release of pro-inflammatory cytokines, and the creation of an anti-inflammatory environment. Chronic inflammation has been shown to play an important role in LC. Few studies have simultaneously examined associations between physical activity and inflammatory factors in relation to LC. The purpose of this study was to examine physical activity and inflammatory factors, such as serum C-reactive protein (CRP), smoking, and obesity in relation to LC fatality. Methods: Data from cancer-free individuals over age 40 in the Third National Health and Nutrition Examination Survey (1988-1994) were prospectively examined in relation to physical activity, inflammation and LC fatality. Mortality status was ascertained through probabilistic record matching using the National Death Index. Physical activity was assessed in the NHANES III Household Adult Questionnaire, along with demographics, smoking and other lifestyle factors. Cox proportional hazards regression models assessed the relationship between physical activity, inflammatory factors and risk of LC death. Results: Of 8,950 participants, 219 individuals died of LC during the 218-month follow-up period. Multivariate regression analyses revealed a 35% reduced risk of LC death for smokers (HR=0.65, p=0.0061) and 34% reduced risk of LC death for males (HR=0.66, p=0.0230) who reported that they had walked at least a mile or more in the past month versus those who did not report walking a mile or more in the past month, while adjusting for CRP, smoking, age, gender, and BMI. A dose-response effect was observed for low, moderate and high CRP levels and LC death (CRP<3, CRP=3-7, CRP>7, respectively; p-trend<0.0001). No significant associations between physical activity and LC death were observed for non-smokers and females in the adjusted models. Conclusions: This study showed substantial reductions in risk of LC death among smokers and males who reported that they walked at least a mile or more in the past month when adjusting for other inflammation-related factors, which has not been previously examined. These results were not observed for females and non-smokers, however, which may suggest a different mechanism in these groups, such as environmental or genetic factors. Additional studies are needed to further explore these results among diverse populations. Citation Format: Marisa A. Bittoni, Randall E. Harris, Janet Buckworth, Steven K. Clinton, Brian C. Focht. Physical activity and the risk of lung cancer death: Results from the Third National Health and Nutrition Examination Survey. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5043. doi:10.1158/1538-7445.AM2014-5043