The effectiveness and durability of oral semaglutide (S) for treating 103 outpatients with type 2 diabetes mellitus were retrospectively investigated in clinical practice. After the administration of oral S, the body weight and BMI were significantly lower after 1 and 3 months, and HbA1c was significantly lower after 3 months than before administration. In 69 patients in whom oral S had been initiated instead of DPP-4 inhibitors, HbA1c declined significantly after 3 months with no significant change after 1 month. In 32 of 69 patients, the dosage of oral S increased after 1 month, and HbA1c declined significantly from 1 month to 3 months. Although 14 patients complained of nausea, 6 patients had vomiting, and 5 patients had diarrhea, none except for one patient was obliged to discontinue the medication for 3 months. In real-world clinical practice, the effectiveness of oral S on body weight, BMI, and HbA1c has been demonstrated even in patients who switched from DPP-4 inhibitors. Oral S is therefore expected to be a novel therapeutic strategy for patients with type 2 diabetes.