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Background: Reduction in door-to-needle (DTN) times in patients with acute ischemic stroke treated with tissue-type plasminogen activator is associated with improved outcomes. We hypothesized that a learning collaborative would rapidly reduce DTN times at Chicago's primary stroke centers.Methods and Results: We analyzed data from all adult patients with out-of-hospital ischemic stroke hospitalized between January 1, 2010 and March 31, 2015 and who received tissue-type plasminogen activator in the emergency department at 15 primary stroke centers in Chicago and 15 primary stroke centers in St. Louis. We implemented a structured learning collaborative in Chicago in quarter 1 of 2013 that included (1) a quality improvement leader, (2) stroke content expert, (3) multidisciplinary teams from each site, (4) a targeted goal for the program (DTN time <60 minutes in >50% of patients treated with tissue-type plasminogen activator), and (5) face-to-face meetings with on-site visits. We used interrupted time-series analysis to compare the impact of the learning collaborative on DTN times in Chicago pre- and post implementation and also concurrently versus St. Louis. We prespecified adjustment for mode of arrival, emergency medical services prenotification, and onset-to-arrival times. P values less than 0.05 were considered significant. In adjusted analysis, the reduction in DTN time within 1 quarter of implementation was 15.5 minutes (P=0.046) at Chicago sites versus 1.17 minutes at St. Louis sites (P=0.601).Conclusions: Using a learning collaborative model at Chicago's 15 primary stroke centers, we observed major reductions in DTN times within 1 quarter of implementation. Regional collaboration and best practices sharing should be a model for rapid and sustainable system-wide quality improvement. [ABSTRACT FROM AUTHOR]