Abstract Background: Benzene is classified as a Group 1 carcinogen in humans. A major pathway of benzene exposure is through inhalation of ambient air contaminated by emissions from motor vehicle exhaust, gas stations, industry, tobacco smoke, and other consumer products. Prior studies of benzene and lung cancer have been limited largely to occupational studies. We examined the association between outdoor air exposure to benzene and lung cancer risk in the large population-based Multiethnic Cohort Study (MEC), including four major U.S. racial/ethnic groups—African Americans, Latinos, Japanese Americans, and Whites. Methods: Ambient benzene exposure was estimated from EPA data from air monitoring stations that were within 20 km of residences of 97,288 MEC participants, largely from Los Angeles County, from the time-period of recruitment (1993-1996) through 12/31/2013. Cox proportional hazards models were used to examine the associations between time-varying benzene exposure and lung cancer risk (cases=2796), adjusting for age, sex, race/ethnicity, smoking, family history of lung cancer, marital status, education, occupation, use of nonsteroidal anti-inflammatory drugs, body mass index, alcohol consumption, physical activity, intake of total calorie, red and processed meats, and neighborhood (block group) socioeconomic status. Stratified analyses were conducted by sex, race/ethnicity, and smoking status. In addition, subgroup analysis was conducted by histologic cell-type (adenocarcinoma, squamous cell carcinoma, small cell carcinoma, large cell, and not otherwise specified carcinoma). Results: Ambient benzene exposure was associated with increased risk of lung cancer (per 1 ppb hazard ratio (HR)=1.18; 95% CI: 1.03-1.35). Slightly higher hazard ratios were observed in females (HR=1.28; 95% CI: 1.05-1.56) in comparison to males (HR=1.12; 95% CI: 0.92-1.35). There was evidence of heterogeneity in associations by race/ethnicity (p heterogeneity=0.02). Specifically, benzene exposure was associated with increased lung cancer risk among African Americans, Japanese Americans, and Latinos (HR ranged 1.18 to 1.42 per 1 ppb), but was inversely associated with risk among Whites. Also, similar associations were seen among ever smokers (HR=1.19; 95% CI: 1.03-1.37) and never smokers (HR=1.25; 95% CI: 0.82-1.89). Across histologic-cell types, a borderline statistically significant association was seen with adenocarcinoma, the most common cell type (HR=1.25, 95% CI: 0.99-1.58). A smaller hazard ratio was observed for squamous cell carcinoma, the stronger smoking-related cell type (HR=1.09, 95% CI: 0.81-1.47). Conclusions: Benzene exposure adversely impacts the risk of lung cancer in the general population but particularly in non-Whites after adjusting for smoking, occupational and other exposures. Additional large population-based studies are needed to confirm this finding and reinforce the need for stringent clear air laws. Citation Format: Iona Cheng, Chiuchen Tseng, Jun Wu, Juan Yang, Salma Shariff-Marco, Jennifer Jain, S. Lani Park, Scott Fruin, Timothy Larson, Scarlett Lin Gomez, Lynne Wilkens, Daniel Stram, Loic Le Marchand, Beate Ritz, Anna H Wu. Association between benzene, a hazardous air pollutant, and lung cancer risk: The Multiethnic Cohort Study [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C052.