The prevalence of atrial fibrillation (AF) in patients with heart failure is high, but data about the effects of cardiac resynchronization therapy (CRT) in patients with chronic AF are scarce. In this prospective observational study of 263 consecutive patients, CRT was performed in 96 patients (37%) with chronic AF and 167 patients (63%) with sinus rhythm (SR). Echocardiographic and clinical parameters were evaluated at baseline and 3 and 12 months. Reverse left ventricular (LV) remodeling is defined as LV end-systolic volume decrease > or =10%. Hospitalization rates for heart failure in the year before and after implantation were compared. Baseline characteristics between patients with and without AF were similar, but the AF group had smaller LV end-systolic and end-diastolic volumes and larger left atrial dimensions. New York Heart Association class, 6-minute walking distance, quality-of-life score, LV ejection fraction, and mitral regurgitation improved significantly at 3 and 12 months in both groups, and the changes were similar. Reverse LV remodeling after 3 and 12 months was 74% and 82% (AF group) versus 77% and 83%, respectively (SR group, p = 0.79). After 1 year, cardioversion had occurred in 25% of patients with AF. In the year after implantation, significant decreases in hospitalizations for heart failure in both groups (84% and 90%) were documented. Long-term mortality was almost equal in both groups. In conclusion, this large-scale study shows that the benefit of CRT in patients with chronic AF and heart failure is similar to that in patients with SR. Patients with chronic AF and heart failure should be considered candidates for CRT.