Background and aims: The pharmacological treatment of type 2 diabetes mellitus (T2DM) relies on diverse glucose-lowering medications, championing Sodium-Glucose Cotransporter-2 inhibitors (SGLT2i) and Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) as viable options to address concurrent cardiovascular risk. An oral formulation of semaglutide has been developed and introduced to clinical use for managing T2DM only recently. As such, there is a relative paucity of practice evidence while building experience on its combination with SGLT2i. Therefore, we sought to gather real-world data on effectiveness and safety of oral semaglutide as add-on therapy in poorly controlled T2DM on background SGLT2i. Methods: We retrospectively analyzed 142 (66% males, 68% older than 60 years, 85% overweight/obese) consecutive outpatients in a multi-center study involving a network of diabetes referral centers. Results: After 6.8±2.6 (mean ±SD) months of treatment, both glycosylated hemoglobin (HbA1c) and fasting plasma glucose levels significantly improved: 39.6% of patients achieved HbA1c DCCT≤7% and 18.8% experienced both a decrease of HbA1c≥1% and a weight loss ≥5%. In addition, body weight, body mass index, waist circumference, triglycerides, and total cholesterol levels were significantly reduced. Regarding safety, 94.7% of reported adverse events (19 in total) were non-serious gastrointestinal symptoms and 1 patient experienced hypoglycemia. Conclusions: The herein presented real-world data suggest that oral semaglutide can be regarded as safe and effective, when used as add-on medication for uncontrolled T2DM on background SGLT2i.