Key PointsQuestionWhat is the effect of a problem-oriented, culturally adapted, targeted quality improvement intervention on reperfusion therapy, including intravenous thrombolysis or endovascular thrombectomy, for acute ischemic stroke in China?FindingsIn this stepped-wedge cluster randomized clinical trial of 12 132 patients with acute ischemic stroke who were enrolled within 3.5 or 4.5 hours of onset from 16 secondary and 33 tertiary hospitals, the rate of reperfusion therapy for eligible patients was 53.5% in the intervention period and 43.9% in the control period; the improvement was not statistically significant after adjusting for cluster and period, but it was statistically significant when limited to the setting of secondary hospitals.MeaningAmong patients with acute ischemic stroke in China, a targeted quality improvement intervention did not improve the reperfusion therapy rate compared with usual care but may be effective in secondary hospitals, which may provide a direction for better resource allocation.