Abstract The present analysis is aimed to evaluate the use and results of direct oral anticoagulants (DOACs) in the past years, in a group of patients presenting with multiple comorbidies and at medium–high thromboembolic risk. In the past years, our outpatient Center followed 929 patients (mean age at admission 76.5 + 9.2 years, range: 29–99 years, 501 men), 848 with non–valvular atrial fibrillation/flutter, and 81 with recent phlebopulmonar thromboembolism (PPTE). An anamnesis of previous cardiovascular events were present in 302 patients (32.5%): coronary artery disease (146), carotid or peripheral atherosclerosis (109), cerebral stroke or ischemia (116). Initial CHA2DS2–VASc and HASBLED score were respectively 3.9 and 2.3 points. Patients were initially treated with Apixaban (A) (301, 89 with reduced dose, according to clinical–prescriptive characteristics), Dabigatran (D) (332, 256 with low dose), Edoxaban (E) (161, 83 with reduced dose), Rivaroxaban (R) (135, 53 with reduced dose). All patients were followed–up periodically (every 6 months) with both clinical and instrumental controls (electrocardiogram, blood tests, etc.), re–evaluating risk factors, in order also to check indication and dosage appropriateness. After a mean follow–up of 3.8 years (range: 6 montsh–9 years), for a total of 3530.2 years*patient, 57 patients (6.1%) had stopped DOAC therapy, because of: severe renal failure (12), repeated bleeding (6), clinical criteria (19), mechanical valve insertion (7), detection of thrombophilia (5), left atrial appendage occlusion (3), frailty (5). In the remaining 872 patients, 33 strokes (7 relapses), 11 PPTE, 17 major bleedings, 24 clinically relevant bleedings, and 71 minor bleedings, occurred. DOAC dose reduction occurred in 101 patients (11.6%: 31on A, 25 on D, 16 on E, 29 on R), because of clinical criteria (28), renal failure (56), bleedings (17). A replacement with other DOACS occurred in 104 patients (11.9%: 7 on A, 71 on D, 5 on E, 21 on R), because of renal failure (29), digestive disorders (27), bleedings (32), thrombotic events (6), lactose intolerance (3), allergic reactions (7). Clinical–and instrumental periodical control of patients treated with DOACs confirmed their effectiveness and safety, even in a population at medium–high thromboembolic risk. Additionally, such a management may allow also a greater prescribing appropriateness, as well as a safer and reliable follow–up over time of these patients.