Introduction: The SAFER approach using apnea-at-end-of-expiration/right-ventriculography has been described recently, showing high success rates with an excellent safety profile. Anticoagulation management during epicardial-access (EA) cardiac procedures remains controversial, with guidelines recommending its discontinuation to mitigate procedural risks. However, some patients have compelling indications for uninterrupted periprocedural anticoagulation.Objective: To determine the efficacy and safety of the SAFER epicardial approach in patients on uninterrupted oral anticoagulation (OAC).Methods: In this prospective multicenter study, patients who underwent EA with the SAFER technique for ventricular tachycardia (VT) ablation or left atrial appendage occlusion (LAAO) from June 2021 to November 2023 were included. The primary efficacy outcome was successful EA, while the safety outcome was a composite of procedural-related complications. Secondary outcomes included procedural characteristics and other acute and long-term complications.Results: A total of 40 patients were included (VT ablation=28, LAAO=12) in the analysis (mean age 63.82{plus minus}12.8 years, male 73%). The most prevalent comorbidities among the patients were structural heart disease (65%), and hypertension (62.5%). Almost all patients were on direct OAC (92.5%), while only 7.5% were on warfarin. EA was successfully obtained in 100% of patients with a mean time of 7.9{plus minus}4.79 minutes and a total procedural time of 229.5 (178.2-293.5) minutes. There were no major procedural-related complications.Conclusion: The SAFER epicardial approach is feasible and safe in patients under uninterrupted OAC when the risk of thromboembolic events is high. This consideration should be part of procedural planning, particularly in patients at high risk of stroke or systemic embolism undergoing EA procedures.