Introduction: Persistent atrial fibrillation (PerAF) ablation has been associated with significant recurrence rates which could reflect progressive AF-related atrial remodeling. We hypothesized that the first-diagnosis to ablation time for PerAF is a major determinant of success rates and in direct association with pathways of atrial remodeling. Methods: Two-year outcomes were assessed in 1241 patients undergoing first time ablation of PerAF between January 2005 and December 2012 at our institution. The time intervals between the first diagnosis of PerF and the ablation procedures were determined. Patients had echocardiograms and measures of B-type natriuretic peptide (BNP) and C-reactive protein (CRP) before the ablation procedures. During ablations, patients with atrial scarring by voltage were identified. Results: The median time-to-ablation since the first PerAF diagnosis was 3 years (interquartile range 1-6.5). With longer diagnosis-to-ablation time (based on quartiles), there was a significant increase in BNP levels (p=0.01), CRP levels (p<0.0001), left atrial size (p=0.03) and scarring (p=0.04). Atrial arrhythmia recurred after a single ablation in 555 patients (44.7%); and 364 (29.3%) underwent repeat ablations. At last follow-up, 1005 patients (81.0%, 390 on antiarrhythmic medications) were either arrhythmia free or had their arrhythmia controlled. In Cox Proportional Hazard analyzes, BNP levels, CRP levels, left atrial size and scarring were associated with arrhythmia recurrence. The diagnosis-to-ablation time had the strongest association with success rates which persisted in multivariate Cox analyzes (HR for recurrence per +1Log diagnosis-to-ablation time 1.25, 95%CI 1.11-1.42, p<0.0001; 4th vs. 1st quartile 2.27, 95%CI 1.52-3.47, p<0.0001). Conclusions: The success rates with PerAF ablation are highest with early intervention, that is ablation before the progression of atrial remodeling.