Background: Semaglutide is the first once-daily oral GLP-1 receptor agonist (GLP-1 RA) for type 2 diabetes mellitus (T2DM) and has been available in Italy since 2022. Aim: To evaluate the metabolic control and tolerability of oral semaglutide in patients with T2DM, in addition to current hypoglycemic therapy. Materials and methods: A retrospective evaluation was performed on the anthropometric and biochemical data of 120 diabetic patients (81 M, 32 F), aged 64.7± 9.1 years. T2DM duration was 11.2±7.1 years. Patients followed at the Outpatient Clinic Diabetologia of ASST Bergamo Ovest, were consecutively treated with oral semaglutide in addition to their usual hypoglycemic therapy. The initial dose was 3 mg/day, and after 4 weeks it was increased to 7 mg/day, as per the drug’s technical data sheet. The mean follow-up period from the start of treatment was 6.2±1.7 months. All data are expressed as mean±standard deviation. Results: A significant reduction was documented compared to baseline in weight (from 84.5±15.8 kg to 82.8±15.8 kg; p<0.0001), BMI (from 30.7±10.2 to 29.2±4.9 kg/m2; p=0.05), HbA1c (from 61.5±11.6 to 55.1±12.6 mmol/mol; p<0.0001), fasting blood glucose (154.9±35.6 to 140.5±33.4 mg/dL; p<0.0001) and LDL Cholesterol (89.9±33.1 to 82.2±30.6 mg/dL; p<0.0001). Five patients (4%) out of those considered discontinued oral semaglutide, and 16 patients (13%) reduced the dose to 3mg/day (due to gastric intolerance). Conclusions: Our data confirm the beneficial effect of oral semaglutide on metabolic control and body weight in patients with type 2 diabetes mellitus. The treatment showed a good safety and tolerability profile. In our real-life experience, oral semaglutide confirms itself as a valid treatment option, an alternative to injectable GLP-1 RA therapy.