Objectives The purpose of this study was to perform a systematic review and meta-analysis of prospective randomized clinical trials of cardiac resynchronization therapy (CRT) versus implantable cardioverter-defibrillator (ICD) in patients with reduced ejection fraction (EF), prolonged QRS interval, and New York Heart Association (NYHA) functional class I to II heart failure (HF). Background In patients with advanced HF, CRT improves left ventricular (LV) function and reduces mortality and hospitalizations. Recent data suggest that patients with milder HF also benefit from CRT. Methods A meta-analysis of 5 clinical trials including 4,317 patients with NYHA functional class I/II HF was performed. Results Average age of patients was 65 years, and 80% were male. Frequency of all-cause mortality for CRT versus ICD was 8% versus 11.5% (risk ratio [RR]: 0.81; 95% confidence interval [CI]: 0.65 to 0.99, p = 0.04); for HF hospitalization, it was 11.6% versus 18.2% (RR: 0.68; 95% CI: 0.59 to 0.79, p < 0.001). Patients assigned to CRT had a significantly greater improvement in LVEF (+ 5.9% vs. +2.2%, p < 0.001) and LV volume than ICD patients. Among mildly symptomatic (NYHA functional class II) patients, CRT was associated with significantly lower mortality and HF hospitalization (RR: 0.73; 95% CI: 0.64 to 0.83), p < 0.001). In asymptomatic (NYHA functional class I) patients, HF hospitalization risk was lower (RR: 0.57; 95% CI: 0.34 to 0.97, p = 0.04) with CRT; however, there was no difference in mortality. Twelve asymptomatic HF patients needed to be treated with CRT to prevent 1 hospitalization. Conclusions Cardiac resynchronization therapy decreases all-cause mortality, reduces HF hospitalizations, and improves LVEF in NYHA functional class I/II HF patients. Although there was a reduction in HF hospitalization with CRT for asymptomatic (NYHA functional class I) patients, risks versus benefits have to be carefully considered in this subgroup. (J Am Coll Cardiol 2011; 58: 935-41) (C) 2011 by the American College of Cardiology Foundation