Combined sewer overflow (CSO) events release untreated wastewater into surface waterbodies during heavy precipitation and snowmelt. Combined sewer systems serve people in the United States, primarily in urban and suburban municipalities in the Midwest and Northeast. Predicted increases in heavy precipitation events driven by climate change underscore the importance of quantifying potential health risks associated with CSO events. The aims of this study were to a) estimate the association between CSO events (2014-2019) and emergency department (ED) visits for acute gastrointestinal illness (AGI) among Massachusetts municipalities that border a CSO-impacted river, and b) determine whether associations differ by municipal drinking water source. A case time-series design was used to estimate the association between daily cumulative upstream CSO discharge and ED visits for AGI over lag periods of 4, 7, and 14 days, adjusting for temporal trends, temperature, and precipitation. Associations between CSO events and AGI were also compared by municipal drinking water source (CSO-impacted river vs. other sources). Extreme upstream CSO discharge events (th percentile by cumulative volume) were associated with a cumulative risk ratio (CRR) of AGI of 1.22 [95% confidence interval (CI): 1.05, 1.42] over the next 4 days for all municipalities, and the association was robust after adjusting for precipitation [1.17 (95% CI: 0.98, 1.39)], although the CI includes the null. In municipalities with CSO-impacted drinking water sources, the adjusted association was somewhat less pronounced following 95th percentile CSO events [ 1.05 (95% CI: 0.82, 1.33)]. The adjusted CRR of AGI was 1.62 in all municipalities following 99th percentile CSO events (95% CI: 1.04, 2.51) and not statistically different when stratified by drinking water source. In municipalities bordering a CSO-impacted river in Massachusetts, extreme CSO events are associated with higher risk of AGI within 4 days. The largest CSO events are associated with increased risk of AGI regardless of drinking water source. https://doi.org/10.1289/EHP14213.