The aim of this study is to assess serum human epididymis protein 4 (HE-4) levels as a biomarker for predicting the recurrence of atrial fibrillation (AF) after catheter ablation. This was a prospective observational study that enrolled one hundred eighty-four consecutive nonvalvular AF patients (65 persistent, 119 paroxysmal) who were eligible for their first ablation. Multiple Cox proportional hazards models and Kaplan–Meier curve analyses were used to test the association between serum HE-4 levels and AF recurrence after catheter ablation. During the 12-month follow-up, we observed that 47 patients (25.5%) experienced AF recurrence. Patients were divided into tertiles of HE-4 level (T1: < 50 pmol/L; T2: ≥ 50 pmol/L). The AF recurrence rate of higher serum HE-4 level patients was significantly increased (34.6% vs 13.8%, P < 0.001). Generalized additive models were used to visually assess functional relationships between the serum HE-4 levels and the risk of AF recurrence. When stratified with serum levels as the cut-off value, Kaplan–Meier analysis showed that patients with serum HE-4 levels (> 50 pmol/L) had a significantly increased risk of AF recurrence. In addition, multivariate Cox proportional hazard modelling revealed that HE-4 (≥ 50 pmol/L) (HR 2.65; 95% CI 1.34, 5.27, P = 0.005) was independent predictors of AF recurrence. Serum HE-4 levels in patients with AF are associated with postoperative recurrence of AF, and high HE-4 levels are an independent predictor of AF recurrence after ablation.