Objectives The purpose of this study was to test whether a microcatheter can safely be advanced across the right atrial appendage to access the pericardium and then withdrawn despite subsequent high-intensity anticoagulation. We also tested whether transatrial pericardial insufflation of carbon dioxide (CO2) would enhance the safety of subxiphoid needle access to the empty pericardium by separating the heart from the anterior pericardium. Background Subxiphoid needle access to the empty pericardium, required for left atrial suture ligation and epicardial ablation for rhythm disorders, risks myocardial or coronary laceration. Methods A catheter from the femoral vein engaged the right atrial appendage for angiographic confirmation of position. Through that catheter, the back end of a 0.014- or 0.018-inch guidewire crossed the right atrial wall to enter the pericardium and delivered a 2.4-F microcatheter. CO2 1 to 2 ml/kg was insufflated into the pericardium immediately before subxiphoid needle access under lateral projection fluoroscopy. Thirteen patients undergoing subxiphoid suture ligation of the left atrial appendage consented to participate in this research protocol. Results Right atrial exit succeeded in 11 subjects (85%) and failed uneventfully in 2 subjects. CO2 insufflation of 96 ± 22 ml achieved 12 ± 4 mm separation of the anterior pericardium from the myocardial wall, allowed rapid and successful subxiphoid anterior needle and guidewire entry in all 11 subjects, and did not have any evident hemodynamic effects. The immediate pericardial aspirate was serous in all but 1 subject. Conclusions We report the first human intentional transatrial exit procedure. Transatrial microcatheter access to the pericardium can be achieved safely. Pericardial insufflation with CO2 makes subxiphoid access to the empty pericardium rapid and safe. Although our clinical experience to date remains small, with further experience, this approach may prevent the life-threatening complications of "dry" subxiphoid pericardial access.