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Current guidelines recommend atrioventricular junction (AVJ) ablation in patients with atrial fibrillation (AF) treated with cardiac resynchronization therapy (CRT). Our study compared the CRT response of patients in sinus rhythm (SR) vs. AF.In this observational, prospective, multicentre study, patients were grouped by intrinsic rhythm. For the first 2 months, the negative chronotropic drug was optimized in the AF group. If ventricular pacing was ≤85%, AVJ ablation was recommended. Responders were defined as patients who survived without requiring heart transplant and had a ≥ 10% reduction in left ventricular end-systolic volume (LVESV) at 12 months after implantation. Of 202 patients included, 156 (77%) were in SR and 46 (23%) had AF. After drug optimization, only 13/46 (28%) of the AF patients required AVJ ablation (AF + AVJ). The percentage of responders was 83/156 (53%) for SR vs. 22/46 (48%) AF (P = 0.4). Among AF patients the response was 16/33 (48%) for AF with non-AVJ ablation vs. 6/13 (46%) AF + AVJ, P = 0.56. The LVESV decreased in all three groups: –30 ± 39 mL, –24 ± 43 mL, and –22 ± 36 mL, respectively (P = 0.75). Mortality was higher in patients with AF compared with SR: 10/46 (21%) vs. 9/156 (5.7%), log rank 10.6, P <0.05.Although only 28% of the patients in AF had the AVJ ablated, there were no differences in the percentage of response and echo improvement between patients in SR and AF. However, mortality was higher in patients with AF compared with patients in SR.