Abstract Background Catheter ablation is an effective rhythm control therapy for atrial fibrillation (AF). Recent advancements in technology have improved the efficacy and safety of this procedure. Current European Society of Cardiology and Japanese Circulation Society guidelines recommend that catheter ablation (CA) for patients with paroxysmal AF (PAF) after failure of drug therapy is classified as Class I, and CA as first-line therapy is categorized as Class IIa. However, there are limited clinical studies directly comparing these groups. Objective This study aimed to compare the efficacy and safety of CA as first-line therapy vs. those after failed drug therapy using data from the Japan Nationwide Ablation (J-AB) Registry led by the Japanese Heart Rhythm Society. Methods Detailed data of patients who underwent catheter ablation for PAF extracted from the J-AB registry were analyzed. Patients were divided into two groups: those who underwent CA as first-line therapy (First-line group) or those who underwent CA after failed drug therapy (Drug failure group). Patients’ characteristics, efficacy and safety of CA were compared between the two groups. Efficacy was assessed by evaluating the recurrence rate of any atrial arrhythmia within one year after the 90-day blanking period, and major safety outcomes were set as severe bleeding complication, stroke, and gastrointestinal disorders during the perioperative period. Result This analysis included 5,011 cases with a median age of 69 years (range 61-75) and 35% females. Comparing patient characteristics between the first-line therapy group (n = 3,447) and the drug failure group (n = 1,564), there are no statistically significant differences between the two groups except in left atrium diameter in echocardiogram (LAD) (38 [34-42] mm vs. 38 [34-43] mm, P <0.001), serum creatinine levels (0.8 [0.7-1.0] mg/dl vs. 0.9 [0.7-1.0] mg/dl, P <0.001), and beta-blocker usage (38.2% vs. 46.7%, P <0.01). A total of 501 recurrence events were observed in this analysis during a median follow-up of 365 [254-390] days. Recurrence rates did not statistically differ between the two groups (log-rank P=0.49). After adjusting for contributing factors with age, gender, body mass index, LAD, and left ventricular ejection fraction in echocardiogram using a multivariate Cox proportional hazards model, efficacy outcomes showed no significant difference between the two groups (adjusted hazard ratio; 1.06 95% confidence interval; 0.88-1.28, P = 0.55). Besides, the two groups had no significant difference in major safety outcomes. Conclusions Catheter ablation as the first-line therapy for paroxysmal atrial fibrillation showed a similar recurrence rate of atrial arrhythmias and adverse events compared to those who underwent catheter ablation after drug failure.