We sought to determine the effects of cardiac resynchronization therapy (CRT) in New York Heart Association (NYHA) functional class II heart failure (HF) and NYHA functional class I (American College of Cardiology/American Heart Association stage C) patients with previous HF symptoms. Cardiac resynchronization therapy improves left ventricular (LV) structure and function and clinical outcomes in NYHA functional class III and IV HF with prolonged QRS. Six hundred ten patients with NYHA functional class I or II heart failure with a QRS > or =120 ms and a LV ejection fraction < or =40% received a CRT device (+/-defibrillator) and were randomly assigned to active CRT (CRT-ON; n = 419) or control (CRT-OFF; n = 191) for 12 months. The primary end point was the HF clinical composite response, which scores patients as improved, unchanged, or worsened. The prospectively powered secondary end point was LV end-systolic volume index. Hospitalization for worsening HF was evaluated in a prospective secondary analysis of health care use. The HF clinical composite response end point, which compared only the percent worsened, indicated 16% worsened in CRT-ON compared with 21% in CRT-OFF (p = 0.10). Patients assigned to CRT-ON experienced a greater improvement in LV end-systolic volume index (-18.4 +/- 29.5 ml/m2 vs. -1.3 +/- 23.4 ml/m2, p < 0.0001) and other measures of LV remodeling. Time-to-first HF hospitalization was significantly delayed in CRT-ON (hazard ratio: 0.47, p = 0.03). The REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) trial demonstrates that CRT, in combination with optimal medical therapy (+/-defibrillator), reduces the risk for heart failure hospitalization and improves ventricular structure and function in NYHA functional class II and NYHA functional class I (American College of Cardiology/American Heart Association stage C) patients with previous HF symptoms. (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction [REVERSE]; NCT00271154).