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This case study presents an interchange alternatives analysis from the Indiana Department of Transportation (INDOT). The analysis supported a multi-agency planning and engineering effort that involved INDOT, the Indianapolis Metropolitan Planning Organization, Hamilton County, Town of Fishers, and City of Noblesville. These agencies identified State Road (SR) 37 from 126th Street in Fishers to SR 32/38 in Noblesville as a candidate for significant mobility and safety improvements. The SR 37 corridor project had two primary needs: 1) reduce existing and forecasted congestion at signalized intersections within the study area, and 2) reduce the crash frequency and rate at identified intersections. INDOT targeted five, at-grade signalized intersections along the study corridor for interchange improvements. The safety analysis applied State-specific safety performance functions (SPFs) and crash modification factors (CMFs) derived from the American Associate of State Highway and Transportation Officials (AASHTO) Highway Safety Manual (HSM) to predict crashes for “Build” and “No-Build” scenarios over a 20-year period between 2018 and 2038. The INDOT analysis encountered several key challenges, including key technical inputs for the Interactive Highway Safety Design Model (IHSDM) software and the application of the HSM to future design alternatives; for instance, INDOT did not apply the Empirical-Bayes (EB) method due to the significant change in the design and operational performance of the corridor between the Build and No-Build scenarios. INDOT’s ingenuity and engineering judgment allowed the agency to navigate many of these challenges, and the analysis predicted that the Build alternative, although originally proposed for its traffic operational improvements, should yield a safety benefit and reduce crashes compared to the No-Build alternative future.