Background and Aim: Drug sustainability (DS) is a surrogate marker for treatment efficacy. We aimed to compare the DS of two main biologics used to treat moderate-to-severe ulcerative colitis (UC), infliximab (IFX) and vedolizumab (VDZ), in a real-world setting. Methods: We conducted a retrospective cohort study at a tertiary medical center in Israel. We included patients treated between 1 December 2017 and 1 May 2021, who were followed for up to 300 weeks. DS was defined as corticosteroid-, surgical-, and hospitalization-free treatment. Results: 217 patients with UC were included. VDZ had a significantly longer median DS of 265.6 weeks compared to IFX’s 106.5 weeks (p= 0.001) in treatment-naïve patients, even when adjusting for disease severity (HR 0.55 95 CI 0.3–0.98,p= 0.042). In treatment-experienced patients, DS was comparable between IFX and VDZ (p= 0.593). Conclusions: VDZ showed significantly longer DS in treatment-naïve patients with UC compared to IFX, also when adjusted for disease severity. There was no difference in DS between VDZ and IFX in treatment-experienced patients and patients switching from one drug to another. VDZ may be a suitable first-line treatment for biologic-naïve patients with moderate-to-severe UC.