Background:Disinfection byproducts (DBPs) and N-nitroso compounds (NOC), formed endogenously after nitrate ingestion, are suspected endometrial carcinogens, but epidemiological studies are limited.Objectives:We investigated the relationship of these exposures with endometrial cancer risk in a large prospective cohort.Methods:Among postmenopausal women in the Iowa Women’s Health Study cohort, we evaluated two major classes of DBPs, total trihalomethanes (TTHM) and five haloacetic acids (HAA5), and nitrate-nitrogen () in public water supplies (PWS) in relation to incident primary endometrial cancer (1986–2014). For women using their PWS at enrollment (; ), we computed historical averages of annual concentrations; exposures were categorized into quantiles and when possible percentile. We also computed years of PWS use above one-half the U.S. maximum contaminant level (; TTHM; HAA5; ). Dietary nitrate/nitrite intakes were estimated from a food frequency questionnaire. We estimated hazard ratios (HR) and 95% confidence intervals (CI) via Cox models adjusted for age, endometrial cancer risk factors [e.g., body mass index, hormone replacement therapy (HRT)], and mutually adjusted for . We evaluated associations for low-grade () vs. high-grade () type I tumors. We assessed interactions between exposures and endometrial cancer risk factors and dietary factors influencing NOC formation.Results:Higher average concentrations of DBPs (95th percentile: TTHM , HAA5 ) were associated with endometrial cancer risk (TTHM: , 95% CI: 1.41, 3.40; HAA5: , 95% CI: 1.19, 2.83; ). Associations were similarly observed for women greater than median years of PWS use with levels , in comparison with zero years (TTHM: , 95% CI: 1.18, 2.21; HAA5: , 95% CI: 1.31, 2.62). Associations with DBPs appeared stronger for low-grade tumors (TTHM: , 95% CI: 1.17, 3.83; ) than for high-grade tumors (TTHM: , 95% CI: 0.80, 2.44; ), but differences were not statistically significant (). Associations with TTHM were stronger among ever HRT users than non-HRT users (). We observed no associations with in drinking water or diet.Discussion:We report novel associations between the highest DBP levels and endometrial cancer for our Iowa cohort that warrant future evaluation. https://doi.org/10.1289/EHP10207