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Background: The objective of the STREAM Trial was to evaluate the effect of simulation training on process times in acute stroke care. Methods: The multicenter prospective interventional STREAM Trial was conducted between 10/2017 and 04/2019 at seven tertiary care neurocenters in Germany with a pre‐ and post‐interventional observation phase. We recorded patient characteristics, acute stroke care process times, stroke team composition and simulation experience for consecutive direct‐to‐center patients receiving intravenous thrombolysis (IVT) and/or endovascular therapy (EVT). The intervention consisted of a composite intervention centered around stroke‐specific in situ simulation training. Primary outcome measure was the 'door‐to‐needle' time (DTN) for IVT. Secondary outcome measures included process times of EVT and measures taken to streamline the pre‐existing treatment algorithm. Results: The effect of the STREAM intervention on the process times of all acute stroke operations was neutral. However, secondary analyses showed a DTN reduction of 5 min from 38 min pre‐intervention (interquartile range [IQR] 25–43 min) to 33 min (IQR 23–39 min, p = 0.03) post‐intervention achieved by simulation‐experienced stroke teams. Concerning EVT, we found significantly shorter door‐to‐groin times in patients who were treated by teams with simulation experience as compared to simulation‐naive teams in the post‐interventional phase (−21 min, simulation‐naive: 95 min, IQR 69–111 vs. simulation‐experienced: 74 min, IQR 51–92, p = 0.04). Conclusion: An intervention combining workflow refinement and simulation‐based stroke team training has the potential to improve process times in acute stroke care. [ABSTRACT FROM AUTHOR]