Introduction: Semaglutide is the first glucagon-like peptide 1 receptor agonist (GLP1-RA) available both as a weekly subcutaneous injection and an oral daily tablet for the treatment of T2DM. Data reporting a comparison in efficacy and persistence between the two formulations in a real-world setting are limited. Methods: This is a single-center, retrospective observational cohort study. Patients with T2DM that started treatment with either formulation between January 1 2019, and July 31 2023 and had at least one follow-up visit at six month were included in the analysis. Patients that stopped treatment with subcutaneous semaglutide due to market shortage and not due to clinical reasons were excluded from the analysis. Results: We included 109 patients in the oral and 121 patients in the subcutaneous semaglutide group, respectively. At baseline, patients in the oral semaglutide group were significantly older (mean age: 67±11 vs 63±11 years, p=0.002) and had a lower body mass index (BMI: 30.5±5.6 vs 33.9±7.1 kg/m2, p<0.001). The proportion of patients persistent to treatment was significantly lower in the oral compared with the subcutaneous group at both 6 and 12 months (72.3% vs 92.4%, Log rank test p<0.001). In a multivariable Cox regression model adjusted for age and BMI, patients in the subcutaneous semaglutide group were at lower risk of discontinuing the medication compared with the oral group (HR 0.30, 95%CI 0.13-0.57, p<0.001). Most common reasons for discontinuation were adverse gastro-intestinal side effects. When adjusted for age and BMI at baseline, body weight reduction (-5.5 kg in both groups) and HbA1c reduction (-0.8 vs -1.1%) were not different. Conclusions: The present real-world study suggests that persistence is significantly lower when semaglutide is administered as a once-daily tablet compared with a weekly injection.