Background: Chronic inflammation has been linked to cancers, and use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risk of several cancers. To further refine the magnitude of NSAID-related associations, in particular for cancers related to inflammation, such as alcohol-, infection-, obesity-, and smoking-related cancers, as well as for less common cancers, we evaluated the use of NSAIDs and cancer risk in a very large cohort. We used propensity scores to account for potential selection bias and hypothesized that NSAID use is associated with decreased cancer incidence. Methods: We conducted a prospective study among 314,522 participants in the NIH-AARP Diet and Health Study. Individuals who completed the lifestyle questionnaire, which included NSAID use, in 1996-1997 were followed through 2006. Information on cancer incidence was ascertained by linking to cancer registries and vital status databases. Findings: During 2,715,994 person-years of follow-up (median 10.1 person-years), there were 51,894 incident cancers. Compared with non-users of NSAIDs, individuals who reported use in the 12 months prior to interview had a significantly lower risk of all inflammation-related cancer, alcohol-related, infection-related, obesity-related, and smoking-related cancers [hazard ratio (HR) (95% CI)) 0.90 (0.87-0.93), 0.80 (0.74-0.85), 0.82 (0.78-0.87), 0.88 (0.84-0.92), and 0.88 (0.85- 0.92) respectively)]. Conclusions: After accounting for potential selection bias, our data showed an inverse association between NSAID use and alcohol-related, infection-related, obesity-related, and smoking-related cancers and support the hypothesis that inflammation is related to an increased risk of certain cancers.