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The aim of this study was to investigate the prognostic value of natriuretic peptides and atrial fibrillation (AF) on response to cardiac resynchronization therapy (CRT) and mortality.This study included 338 consecutive CRT patients. Response to CRT was defined as a reduction in left ventricular end-systolic volume of ≥15% in the absence of death at 6-month follow-up. During follow-up (27 ± 19 months), 139 patients (41%) had AF, being new onset in 40 patients (21%). Forty-two patients (12%) had permanent AF. Response to CRT was observed in 168 of 302 patients (56%): 60 of 123 patients (43%) with AF vs. 108 of 179 patients (60%) without AF (P = 0.047). Low baseline atrial natriuretic peptide (ANP) [odds ratio for log2 ANP 0.49, 95% confidence interval (CI) 0.35–0.68, P < 0.001] and large left ventricular end-systolic volume (odds ratio for every 50 mL 1.40, 95% CI 1.09–1.79, P = 0.009) were independent predictors of response. Neither the presence of AF nor the increase in AF burden independently predicted response. Ninety patients (27%) died; 50 patients (36%) with AF vs. 40 patients (20%) without AF (log rank P = 0.029). Important predictors of all-cause mortality were new-onset AF (hazard ratio 8.11, 95% CI 3.31–19.85, P < 0.001), permanent AF (hazard ratio 3.19, 95% CI 1.61–6.30, P = 0.001), and baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) (hazard ratio for log2 NT-proBNP 0.77, 95% CI 0.66–0.90, P = 0.001).In patients treated with CRT, lower ANP and larger left ventricular end-systolic volume were independent predictors of response. New-onset AF, permanent AF, and NT-proBNP were independently associated with increased all-cause mortality.