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BACKGROUND Cryoballoon ablation (CBA) is gaining increasing acceptance in the treatment of persistent (per) atrial fibrillation (AF). The cardiac autonomic nervous system (ANS) plays a pivotal role in regulation of AF. OBJECTIVE We evaluated the impact of vagal reactions (VRs), as a surrogate marker for ANS modulation, on the outcome of CBA in perAF. METHODS 250 consecutive patients (pts) (63.9±10.0 years old, 70% male) undergoing primary second generation (2G) CBA for perAF were studied. VRs were defined as: bradycardia <40 bpm, asystole or higher degree AV-block. Follow-up (FU) visits at 3, 6 and 12 months (m) included 7-day Holter ECGs. RESULTS VRs were recorded in 61 (24%) pts. These pts showed a significantly reduced recurrence rate of AF (5%) compared to those without VRs (log-rank p<0.01). Univariate Cox regression analyses confirmed VRs as a strong predictor for AF-free survival (p<0.01, hazard ratio (HR) 0.10). Female gender (p=0.02, HR 1.71), pre-procedural tachycardia (p=0.01, HR 1.01) and AF (p=0.01, HR 1.75) prior to CBA upon admission were revealed as predictive for AF recurrence. Multivariate regression model calculation solely identified VRs (p<0.01, HR 0.11, confidence interval (CI) 0.03-0.34) and male gender (p=0.01, HR 0.57, CI 0.36-0.89) as independent predictors (IPs) for AF-free survival. CONCLUSION VR is an independent predictor for AF-free survival after CBA of persistent AF.