BACKGROUND: Combined sewer overflows (CSOs) discharge untreated sewage into surface and recreational water, often following heavy precipitation. Given projected increases in frequency and intensity of precipitation due to climate change, it is important to understand the health impacts of CSOs and mediating effects of sewerage systems. OBJECTIVES: In this study we estimate associations of CSO events and emergency department (ED) visits for gastrointestinal (GI) illness among City of Atlanta, Georgia, residents and explore how these associations vary with sewerage improvements. METHODS: We estimate associations using Poisson generalized linear models, controlling for time trends. We categorized CSOs by overflow volume and assessed effects of CSO events prior to ED visits with 1-, 2- and 3-wk lags. Similarly, we evaluated effects of weekly cumulative precipitation greater than the 90th percentile at the same lags. We also evaluated effect modification by ZIP Code Tabulation Area (ZCTA)-level poverty and infrastructure improvement period using interaction terms. RESULTS: Occurrence of a large volume CSO in the previous week was associated with a 9% increase in daily ED visits for GI illness. We identified significant interaction by ZCTA-level poverty, with stronger CSO-GI illness associations in low than high poverty areas. Among areas with low poverty, we observed associations at 1-wk and longer lags, following both large and lower volume CSO events. We did not observe significant interaction by infrastructure improvement period for CSO- nor precipitation-GI illness associations; however, the number of CSO events decreased from 2.31 per week before improvements to 0.49 after improvements. DISCUSSION: Our findings suggest that CSOs contribute to acute GI illness burden in Atlanta and that the magnitude of this risk may be higher among populations living in areas of low poverty. We did not find a protective effect of sewerage system improvements. Nonetheless, observed reductions in CSO frequency may lower the absolute burden of GI illness attributable to these events. https://doi.org/10.1289/EHP10399.