In 2011 Luzzatto et al. stated that "Paroxysmal nocturnal hemoglobinuria (PNH) is the most vicious acquired thrombophilic state known in medicine". Fourteen years later, although anti-complement therapy reduced the incidence of thrombotic events, their management remains an unmet clinical need. Historically Vitamin K Antagonists were the first-choice medications for anticoagulation in this setting. Nowadays, Direct Oral Anticoagulants (DOACs) are the standard anticoagulant therapy in most settings due to their predictable pharmacokinetics, fixed dosing, and no need for laboratory monitoring. Poor data is available on their use in paroxysmal nocturnal hemoglobinuria patients in the treatment of the acute-phase of venous thromboembolism (VTE), while no data is available on their use in secondary prophylaxis of VTE. We describe our monocentric experience on the management of thrombotic events in PNH patients and on the use of DOACs as secondary prophylaxis medication. Our retrospective monocentric analysis shows that DOACs could be an effective and safe choice in this setting.