Objective: No standard second‐line treatment exists for acute graft‐versus‐host dis‐ease steroid‐refractory (SR‐aGvHD), and long‐term outcomes remain poor. Mesenchymal stromal cells (MSCs) have been evaluated as treatment, but no disease model (DM) exists that integrates and extrapolates currently available evidence. The aim of this study was to develop such a DM to describe the natural history of SR‐aGvHD and to predict long‐term outcomes.Method: The DM was developed in collaboration with experts in haematology‐on‐cology. Subsequently, a model simulation was run. Input parameters for transition and survival estimates were informed by published data of clinical trials on MSC treatment for SR‐aGvHD. Parametric distributions were used to estimate long‐term survival rates after MSCs.Results: The newly developed DM is a cohort model that consists of eight health states. For the model simulation, we obtained data on 327 patients from 14 pub‐lished phase II trials. Due to limited evidence, DM structure was simplified and sev‐eral assumptions had to be made. Median overall survival was 3.2 years for complete response and 0.5 years for no complete response.Conclusion: The DM provides a comprehensive overview on the second‐line treat‐ment pathway for aGvHD and enables long‐term predictions that can be used to perform a cost‐effectiveness analysis comparing any treatment for SR‐aGvHD.