Abstract Background Many prior epidemiological studies have explored the association between aspirin use and cancer risk. Aspirin decreases inflammation by reducing prostaglandin production via the inhibition of the cyclooxygenase-2 enzyme, which may lead to a reduced risk of certain cancers. While most of the studies reporting significant protective effects of aspirin focused on gastrointestinal cancers, there has been a lot of discrepancy in studies examining the association between aspirin use and risk of lung cancer. Racial disparities in the effects of aspirin use on lung cancer risk have not been the focus of previous publications. We used data from a case-control study to evaluate the relationship between aspirin exposure and lung cancer risk among Caucasians and African Americans. Methods Lung cancer cases were identified at one of several clinics, and volunteer controls were recruited from the general community and from the aligned patients of a large health system serving Metropolitan Detroit. Controls were matched to cases based on smoking history (never, 1-20 pack-years or >20 pack-years), race, sex, and 10-year age categories, resulting in 718 cases and 718 controls. Data were collected on participant demographics, history of environmental exposure, smoking history, medical history, family history of cancer, and history of medication (including aspirin) use. Regular use of aspirin was defined as at least three times per week for one month or more during the subject's lifetime. Forward selection was used to determine the set of covariates significantly associated with lung cancer, and these covariates were modeled using conditional multivariable logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI). Aspirin use risk estimates were adjusted for education, chronic obstructive pulmonary disease (COPD) status, current body mass index (BMI), cardiovascular disease (CVD), pack-years and family history of lung cancer. The association between aspirin use and lung cancer risk was then evaluated by race. Results There was no significant association between lung cancer risk and aspirin use in the total sample after adjustment (OR=0.92, p=0.52). However, there was a significant interaction between race and any aspirin use, adjusted for covariates (p=0.03). The direction of the relationship between aspirin use and lung cancer risk differed between African Americans (OR=1.57, 95% CI 0.97-2.54) and whites (OR=0.74, 95% CI 0.54-1.01), although the race-specific odds ratios were not significant. Whites were more likely to report any aspirin use (58%) than African Americans (48%) (p=0.0007), although among ever users there was no significant difference in duration of aspirin use (p=0.21). We further observed a marginally significant interaction between race and baby aspirin use on lung cancer risk (p=0.06), but not between race and adult aspirin use (p=0.67). Conclusion Our results suggest that, in a well-matched sample of lung cancer cases and controls, there is no risk-reducing effect of aspirin use overall, yet the effect of aspirin on lung cancer risk may differ between African Americans and whites, such that the risk-reducing effects may be restricted to whites. This may be due to the lower prevalence of aspirin usage in our sample of African Americans compared to whites, as well as differences in co-morbidities between races. Differences in co-morbidities and associated aspirin use between cases and controls by race will be further explored to explain the heterogeneity of the effects of aspirin use on lung cancer risk. Citation Format: Stephanie S. Pandolfi, Angela S. Wenzlaff, Christine M. Lusk, Elyse Reamer, Christine Neslund-Dudas, Ayman O. Soubani, Shirish M. Gadgeel, Ann G. Schwartz. Relationship between aspirin use and lung cancer risk differs based on race. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B54.