Transesophageal echocardiography (TEE) is recommended in patients undergoing atrial fibrillation (AF) ablation, but use of this strategy is variable. To evaluate whether TEE is necessary before AF ablation in patients treated with novel oral anticoagulants (NOACs). We performed a prospective multicenter registry of AF patients undergoing radiofrequency catheter ablation on uninterrupted NOACs (apixaban and rivaroxaban). All patients were on NOACs for at least 4 weeks before ablation. Heparin bolus was administered to all patients before transseptal catheterization to maintain a target activated clotting time above 300 seconds. A subset of 86 patients underwent brain diffuse magnetic resonance imaging (dMRI) to detect silent cerebral ischemia (SCI). A total of 970 patients (514 53% apixaban patients and 456 47% rivaroxaban patients) were enrolled for this study. The mean age was 69.5 ± 9.0 years, with 824 patients (85%) having nonparoxysmal AF, and 636 patients (65.6%) were male. The average CHA2DS2-VASc score was 3.01 ± 1.3 and CHADS2 score was ≥2 in 609 patients (62.8%). Intracardiac echocardiogram ruled out left atrial appendage thrombus in all patients whose left atrial appendage was visualized (692, 71%), and detected "smoke" in 407 patients (42%). SCI at postprocedure dMRI was detected in 2.3% (2/86). One thromboembolic event (transient ischemic attack) (0.10%) with positive dMRI occurred in a patient on uninterrupted rivaroxaban with longstanding persistent AF. Our study illustrates that performing AF ablation while on uninterrupted apixaban and rivaroxaban without TEE is feasible and safe. This finding has important clinical and economic relevance.