Background: In recent years, non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have been increasingly prescribed to adults with congenital heart disease (CHD) and atrial arrhythmias without good evidence for either safety or efficacy. To address this gap, we initiated an ongoing prospective global registry (NOTE: non-vitamin K antagonist oral anticoagulants for thromboembolic prevention in patients with congenital heart disease). Using the NOTE registry data, the present study aimed to evaluate the occurrence of any adverse events during the initiation phase (first 30 days) of NOACs in adults with CHD and atrial arrhythmias. Methods and Results: For this prospective observational study, 99 adults with CHD and atrial arrhythmias (median age 49 years [IQR 38-61], 53% male) who initiated NOACs at or after the inclusion point were analysed. Thromboembolic events, major bleeding and other minor adverse events were assessed after the first 30 days since the initiation of NOACs. In 54 patients transitioning from VKA to NOACs, 8 minor adverse events (5 minor bleeding; 3 side-effects; 1 drop-out due to minor bleeding) occurred within 30 days after the transition. No adverse events were reported in 46 VKA-naive patients within 30 days after the initiation of NOACs. Conclusions: Initiation of NOACs and transition from VKA to NOACs seem to be safe during the first month, without major adverse events and with only limited minor side effects in adults with CHD and atrial arrhythmias. This global ongoing prospective registry enables precise collection of important clinical information in real-world adults with CHD, managed with NOACs.