Background— The European Cooperative Acute Stroke Study (ECASS) III demonstrated benefit to expanding the intravenous tissue-type plasminogen activator (tPA) window from 3 to 4.5 hours for patients with acute ischemic stroke (AIS). We investigated how this trial influenced use of tPA in clinical practice. Methods and Results— Using the Get With The Guidelines-Stroke data set, we identified 217 692 patients who presented to the hospital within 4.5 hours of AIS from April 2003 to March 2011, 106 113 before and 111 579 after the publication of ECASS III in September 2008. The proportion of patients with AIS who presented within 4.5 hours and were treated with tPA in the 3- to 4.5-hour window increased from 1.2% before ECASS III to 3.5% after ( P <0.0001). The proportion of eligible patients with AIS presenting within 3.5 hours and treated within 4.5 hours increased from 19% (18 484/96 208) to 35% (26 888/77 309) ( P <0.0001). ECASS III appeared to have no adverse affect on the treatment of patients who presented early because the proportion of eligible patients with AIS presenting within 2 hours and treated within 3 hours increased after ECASS III from 57% to 75% ( P <0.0001), whereas median door-to-needle times in patients treated within 3 hours decreased from 79 to 74 minutes ( P <0.0001). Conclusions— Following publication of ECASS III, there has been a significant increase in the use of tPA between 3 and 4.5 hours without adversely affecting treatment of patients in the <3-hour window. However, there remains substantial opportunity to further improve treatment rates in the later time window.