Graft versus host disease (GVHD) is a common complication after hematopoietic cell transplantation (HCT) and associated with significant morbidity and mortality. Preventing GVHD without chronic therapy or increasing relapse is a desired goal. Here, we report a benchmark analysis to evaluate the performance of six GVHD prevention strategies tested at single institutions compared to a large multicenter outcomes database as a control. Each intervention was compared to the control for the incidence of acute and chronic GVHD and overall survival and against novel composite endpoints: acute and chronic GVHD, relapse-free survival (GRFS) and chronic GVHD, relapse-free survival (CRFS). Modeling GRFS and CRFS using the benchmark analysis further informed the design of two clinical trials testing GVHD prophylaxis interventions. This study demonstrates the potential benefit of utilizing an outcomes database to select promising interventions for multicenter clinical trials and proposes novel composite endpoints to be used in GVHD prevention trials.