Abstract Unconventional natural gas development (UNGD) has been rapidly expanding in Pennsylvania since the mid-2000s. The objective was to analyze associations between UNGD exposure during pregnancy and subsequent development of childhood cancer using Pennsylvania birth and cancer registry data. Birth records and childhood cancer registry records that were linked to birth records were obtained through an IRB-approved application process with the Pennsylvania Department of Health. The present analysis included infants born from 2007 to 2015, a period of rapid UNGD expansion in the state. We excluded mothers and their infants living in the most urban areas (i.e., Pittsburgh and Philadelphia), where exposure to many competing pollution sources may confound the analysis. For each mother, an inverse distance weighted (IDW) well count was calculated based on all active wells drilled within a 10-mile radius of the mother’s residence during the one-year period up to the date of birth. Person-years were accumulated for each child from the birth date until either the date of first childhood cancer diagnosis or, for noncases, the end of the study period (December 31, 2016). Cox proportional hazards models were used to investigate associations between IDW well count and hazard ratio (HR) of cancer development among children. There were 812,143 infants born during the study period with complete outcome and covariate data. Of these, there were 859 and 259 children diagnosed with any type of cancer and the most common type, leukemia, respectively. Models were adjusted for infant sex, congenital anomalies, proximity to major roadways, and maternal factors. After adjustment, the hazard ratio of developing any cancer for children born to mothers living in the highest quartile of UNGD exposure was 1.3 (95% confidence interval: 1.0-1.8) compared to the lowest quartile. Childhood leukemia risk was also 1.3 times higher for children born to the most versus least exposed mothers, although the 95% confidence interval was wider (0.8-2.2). In conclusion, children born to mothers living close to UNGD may be at a slightly increased risk for childhood cancer, although the risk is smaller compared to other established risk factors like the presence of a birth defect or older maternal age. As most of the epidemiologic health studies to date have used well density as a surrogate for UNGD exposure, future studies should consider incorporating environmental sampling or personalized monitoring into their exposure assessments. Citation Format: Shaina L. Stacy, Jeanine M. Buchanich, James P. Fabisiak, Linda Robertson, Ravi K. Sharma, Evelyn O. Talbott, Jian-Min Yuan. Unconventional natural gas operations and childhood cancer development in a Pennsylvania birth cohort [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A22.