BACKGROUND: Despite evidence-based national guidelines for optimal treatment of heart failure (HF), the quality of care remains inadequate. We sought to evaluate the effect of a national hospital-based initiative on quality of care in patients hospitalized with HF. METHODS: Two hundred fifty-nine US hospitals participating in the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) submitted data on 48 612 patients with HF from March 1, 2003, through December 31, 2004. Admission, hospital, discharge care, and outcomes data were collected using a Web-based registry that provided real-time feedback on performance measures benchmarked to other hospitals. Process-of-care improvement tools, including evidence-based best-practice algorithms and customizable admission and discharge sets, were provided. RESULTS: Provision of complete discharge instructions and smoking-cessation counseling increased significantly (from 46.8%-66.5% and 48.2%-75.6%, respectively; P < .001 for both). Left ventricular function assessment started at a high rate (89.3%) and improved to 92.1% (P < .001). Angiotensin-converting enzyme inhibitors were prescribed at discharge to 75.8% of eligible patients, which did not improve during the 2-year study. There were trends for reduction of in-hospital mortality, postdischarge death, and combined postdischarge death and rehospitalization and a significant reduction in mean length of stay. Use of preprinted admission order sets and/or discharge checklists increased from 35.6% to 54.1% and was associated with an increase in the use of evidence-based therapies and lower risk-adjusted in-hospital mortality. CONCLUSIONS: Participation in OPTIMIZE-HF was associated with an increase in use of evidence-based therapy, adherence to performance measures, and shorter lengths of stay in patients hospitalized with HF. Increased use of process-of-care improvement tools was associated with further improvements in quality of care. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00344513.