The purpose of this study was to evaluate the feasibility, safety, and outcomes of radiofrequency ablation of atrial fibrillation (AF) in patients with mechanical mitral valve replacement (MVR). The role of ablative therapy in patients with MVR is not yet established, with safety concerns and very few outcome data. Between January 2003 and December 2008, we followed up 81 patients with MVR undergoing first-time AF ablation (compared with 162 age- and sex-matched controls). Arrhythmia recurrences were identified by symptoms with documentation, event monitoring, Holter monitoring, and electrocardiograms. All MVR and control patients underwent ablation under therapeutic international normalized ratio. No entrapment of catheters or stroke occurred. There were no differences in terms of procedure-related complications between the groups (p = NS). Patients with MVR had larger atria (p < 0.0001), lower left ventricular ejection fractions (p = 0.0001), and more concomitant atrial flutter at baseline (p < 0.0001). Over a 24-month follow-up, they had higher recurrence rates compared with controls (49.4% vs. 27.7% after a single ablation, p = 0.0006). The creation of flutter lines significantly reduced recurrences in patients with any history of atrial flutter (16.7% vs. 60.9%, p = 0.009). At last follow-up, 82.7% of MVR patients had their arrhythmia controlled (69.1% not receiving antiarrhythmic drugs). Radiofrequency ablation is feasible and safe for patients with MVR. It allowed restoration of sinus rhythm in a substantial proportion of patients undergoing ablation. An abnormal atrial substrate underlies recurrences in these patients. The ablation procedure needs to be further refined with a focus on extra pulmonary vein triggers and concomitant flutters to improve outcomes.