Simulation is a mainstay of comparative- and cost-effectiveness research when empirical data are not available. The Synthea platform, originally designed for generating realistically coded longitudinal health records for software testing, implements data generation models specified in publicly contributed modules representing patients’ life cycle and disease and treatment progression. We test the hypothesis that Synthea can be used for simulation studies that draw parameters from observational studies and randomized trials. We benchmarked the results and assessed the effort required to create a Synthea module that replicates a recently published cost-effectiveness simulation comparing levofloxacin prophylaxis to usual care for leukemia. A module was iteratively developed using published parameters from the original study; we replicated the initial conditions and simulation endpoints of demographics, health events, costs, and mortality. We compare Synthea’s Generic Module Framework to platforms designed for simulation and show that Synthea can be used, with modifications, for some types of simulation studies.