Background and aims: Semaglutide is the only once-daily oral GLP-1 receptor agonist presently available and, to date, real-world data on its use are limited. Aims of this study were to describe clinical characteristics of patients with type 2 diabetes (T2D) initiating oral semaglutide and to assess its effects on glycemic control and body weight (BW) in routine clinical practice. Materials and methods: This is a real-world retrospective cohort study based on electronic medical records used in an Italian diabetes clinic. Adults with T2D and HbA1c and BW values before oral semaglutide prescription were included. Estimated mean changes in HbA1c and BW after 6 months were evaluated using longitudinal linear mixed models for repeated measures. Treatment discontinuation and safety data were reported. Results: A total of 192 patients initiated oral semaglutide from September 2021 to December 2022. Most patients were male (58%), with a mean age (SD) of 66 (10) years, diabetes duration of 10 (8) years, baseline HbA1c of 7.9 (1.2)% and BW of 82.6 (18) kg. Almost 50% of patients were obese and one-third presented micro and/or macrovascular complications. Baseline glucose-lowering drugs were: metformin (92%), SGLT2 inhibitors (39%), DPP-4 inhibitors (26%), basal insulin (8.8%), injectable GLP-1 RA (6.9%), and sulphonylureas (4.7%). At the first follow-up, most patients (91%) were receiving the 7 mg dose, 9 (6%) were on the 14 mg dose, and 3 (2%) remained on the 3 mg dose. Mean HbA1c and BW changes from baseline to follow-up were -0.7% (95% CI: -0.9 to -0.4; p<0.001) and -2.6 kg (-3.4 to -1.9; p<0.001), respectively. Greater HbA1c reductions were observed in patients with baseline HbA1c 8% (-1.4%, -1.9 to -0.8; p<0.001) and with diabetes duration less than 5 years (-1.5%, -2.2 to -0.8; p<0.005). A total of 40 patients (20.8%) discontinued treatment: 26 (13.5%) because of gastrointestinal adverse events, 10 (5.2%) due to limited effectiveness in lowering HbA1c and/or BW, 1 (0.5%) due to safety concerns of semaglutide use during pregnancy, 3 (1.6%) for unknown reasons. No severe or documented hypoglycemia were reported. Conclusion: In a real clinical setting, T2D patients with suboptimal metabolic control initiating oral semaglutide achieved clinically significant reductions in HbA1c and BW (even on the 7 mg dose). Patients with shorter diabetes duration experienced greater HbA1c reductions, supporting the use of oral semaglutide in the early phase of the disease.