Purpose: The progression from paroxysmal to persistent atrial fibrillation (AF) is associated with an increased prevalence of cardiovascular comorbidities. Plasma atrial and B-type natriuretic peptides are increased in atrial fibrillation. We sought to determine whether mid-regional pro-ANP (MRproANP) and N-terminal pro-brain natriuretic peptide (NTproBNP) can discriminate between paroxysmal vs. persistent lone AF. Methods: We enrolled patients with lone AF (patients aged <60 years without hypertension, diabetes, or structural heart disease). Biomarkers were measured in normal sinus rhythm. We compared the ability of MRproANP versus NTproBNP in discriminating between paroxysmal and persistent lone AF by estimating the area under the ROC curve (AUC). Results: We enrolled 68 paroxysmal and 13 persistent lone AF patients (median age, 48 and 50 years; 88% and 92% male, respectively). Median MRproANP (121.5 v. 56.6 pmol/L, P<0.001) and NTproBNP (292.0 v. 48.0 pmol/L, P=0.004) were higher in persistent than paroxysmal lone AF. MRproANP (AUC [95% CI] 0.82 [0.72-0.92]) was marginally better than NTproBNP (0.76 [0.65-0.88]) in discriminating between paroxysmal and persistent lone AF, P=0.06 (Figure). The AUC of using both markers (0.85 [0.75-0.94]) was not significantly different from MRproANP alone (P=0.08), but was slightly better than NTproBNP alone (P=0.03). Conclusions: MRproANP and NTproBNP may be helpful in discriminating between paroxysmal and persistent lone AF. Further prospective studies are needed to assess whether these biomarkers can predict progression of paroxysmal to persistent lone AF.