This study combined flood-frequency analysis, 1-D (one-dimensional) hydraulic modeling using HEC-RAS, and flood-loss modeling using FEMA's Hazus-MH (Hazards U.S. Multi-Hazard) in order to: 1) quantify how different flood-frequency methodologies affect flood-risk assessments, and 2) quantify the impacts of different floodplain-management scenarios along the Middle Mississippi River (MMR). The nine scenarios tested here included various combinations of flood-frequency methodology, buyouts, and levee configurations. The levee configurations analyzed included: 1) current levee configuration, 2) no levees, 3) a 1500 m levee setback, 4) a 1000 m levee setback, and 5) a customized levee setback designed to maximize protection around existing infrastructure. Two study reaches were chosen: (1) an Urban Study Reach within St. Clair and northern Monroe Counties, IL, with levees designed to withstand the 500-year flood and (2) an Agricultural Study Reach within Union and Jackson Counties, IL, with <100-year levees. A flood-frequency analysis was completed for the St. Louis, MO gauging station, and detailed building inventories were used to estimate flood losses on a structure-by-structure basis (Hazus-MH UDF analysis) for an array of floods ranging from the 2- to the 500-year events. These flood-loss estimates were combined with a stochastic levee-failure model. Finally, estimated flood damages from Hazus-MH were integrated across the full range of flood recurrences in order to calculate expected annual damage (EAD). This study's flood-frequency analysis and corresponding flood-loss assessment demonstrate how differences in flood-frequency methodology can significantly impact flood-risk assessments. EAD based on the UMRSFFS (Upper Mississippi River System Flow Frequency Study) flood frequencies was 68% ($45.4 million) lower than EAD based on this study's flood frequencies. This decrease in EAD demonstrates that the UMRSFFS flood frequencies and corresponding stages may significantly underestimate flood risk within the Urban Study Reach. The 100-year discharge in the UMRSFFS appears to be underestimated by an estimated 17% (187,000 cfs), resulting in a 10% (1.6 m) underestimation of the 100-year flood level. Given the magnitude of the EAD, discharge, and stage differences documented here, a reanalysis of the MMR flood frequencies, flood profiles, and flood maps should be considered. The hydraulic modeling completed here showed that levee setbacks and levee removal successfully reduce stages for all recurrence intervals. For the 100-year flood, average reductions ranged from 0.20 m for a 1000 m levee setback to 1.61 m with levees removed. In general, stage reductions increased with increasing discharge and with increasing setback distance. The flood-level reductions are attributed to increased floodwater storage and conveyance across the reconnected floodplain. Compared to the current conditions, the levee setback and levee removal scenarios tested here reduced flood losses for large, infrequent flooding events but increased flood losses for smaller, more frequent flood events. When combined with buyouts of unprotected structures, levee setbacks reduced flood losses for all recurrence intervals. The 1000 m and 1500 m levee setbacks required buyouts in order to reduce EAD; however, a levee setback carefully planned around existing high-value structures reduced EAD with or without buyouts. The planned levee setback configuration combined with buyouts resulted in the largest decreases in EAD: a $16.8 million (55%) decrease in the Urban Study Reach and an $8.3 million (93%) decrease in the Agricultural Study Reach. Overall, this project showed that levee setbacks in combination with buyouts are an economically viable approach for flood-risk reduction along the study reaches and likely elsewhere where levees are widely employed for flood control. Designing a levee setback around existing high-value infrastructure can maximize the benefit of the setback while simultaneously minimizing the costs. Potentially, this type of planned levee configuration could be used as a template for the replacement of aging or failing levee systems.