Background <p>Outdoor air pollution is a known human carcinogen, but studies of female reproductive malignancies other than breast cancer remain limited.</p> Objective <p>We evaluated associations between outdoor air pollutants and risk of two gynecologic cancers</p> Methods <p>Using nationwide spatiotemporal models, we estimated outdoor residential fine particulate matter (PM_2.5, &lt; 2.5 µm) and nitrogen dioxide (NO₂) concentrations for 140,457 female NIH-AARP Diet and Health Study participants (enrolled 1995–1996), with follow-up through 2018. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for associations between time-varying, 5-year average PM_2.5 and NO₂ concentrations (per 5 µg/m³ and ppb, respectively; 1980–2017) and incident endometrial (<i>n</i> = 3088) and ovarian (<i>n</i> = 1582) cancers, overall and by histologic subtype. Models were adjusted for age and demographic, lifestyle, and neighborhood factors. We evaluated co-pollutant adjustment and effect modification by state (per state-specific interquartile ranges), neighborhood deprivation, and body mass index (BMI).</p> Results <p>We found no relationships with risk of either cancer overall. PM_2.5 was associated with endometrial cancer among participants in Atlanta, Georgia (HR:1.70, CI = 1.16–2.48) and Pennsylvania (HR:1.15, CI = 1.02–1.29). A weaker NO₂ association was apparent in these areas (HR:1.57, CI = 1.11–2.22 and HR:1.10, CI = 0.94–1.28, respectively). Associations with endometrial cancer were suggested in the highest quintile of neighborhood deprivation (HR PM_2.5: 1.05; CI = 0.90–1.22; p-trend=0.07) and HR NO₂:1.06, CI = 1.00–1.12; p-trend=0.02. We found positive, albeit imprecise, ovarian cancer associations in Detroit, Michigan (PM_2.5 HR:1.42, CI = 0.92–2.18 and NO₂ HR:1.72, CI = 0.95–3.13). NO₂ was positively associated with non-endometrioid endometrial cancers (HR:1.12, CI = 0.94–1.35) and PM_2.5 with non-epithelial ovarian tumors (HR:1.50, CI = 0.91–2.47). The impact of co-pollutant adjustment varied across state-specific associations. Relationships did not vary by BMI.</p> Significance <p>We demonstrated modest relationships between air pollutants and risk of endometrial and ovarian cancers for select geographies, neighborhood characteristics, and histologic subtypes. Our findings indicate that future studies should evaluate region-specific factors, including co-varying pollutant distributions.</p> Impact Statement <p>Research on endometrial and ovarian cancers has primarily focused on risk factors such as body mass index and exposure to exogenous and endogenous hormones, particularly unopposed estrogen. We identified suggestive associations between these two cancers and outdoor air pollution exposures, specifically PM_2.5 and NO_2, in specific geographic regions and for certain histologic subtypes. Our novel findings suggest that PM_2.5 chemical constituency and the region-specific air pollution mixture may play a role in the development of these cancers and warrants future investigation.</p>