BACKGROUND AND PURPOSE: Get With The Guidelines (GWTG)-Stroke is a national, hospital-based quality improvement program developed by the American Heart Association. Although studies have suggested improved processes of care in GWTG-Stroke-participating hospitals, it is not known whether this improved care translates into improved clinical outcomes compared with nonparticipating hospitals. METHODS: From all acute care US hospitals caring for Medicare beneficiaries with acute stroke between April 2003 and December 2008, we matched hospitals that joined the GWTG-Stroke program with similar hospitals that did not. Using a difference-in-differences design, we analyzed whether hospital participation in GWTG-Stroke was associated with a greater improvement in clinical outcomes compared with the underlying secular change. RESULTS: The matching algorithm identified 366 GWTG-Stroke-adopting hospitals that cared for 88 584 acute ischemic stroke admissions and 366 non-GWTG-Stroke hospitals that cared for 85 401 acute ischemic stroke admissions. Compared with the Pre period (18-6 months before program implementation), in the Early period (0-6 months after program implementation), GWTG-Stroke hospitals had accelerated increases in discharge to home and reduced mortality at 30 days and 1 year. In the Sustained period (6-18 months after program implementation), the accelerated reduction in mortality at 1 year was sustained, with a trend toward sustained accelerated increase in discharge home. CONCLUSIONS: Hospital adoption of the GWTG-Stroke program was associated with improved functional outcomes at discharge and reduced postdischarge mortality.