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Objectives: We conducted this multicenter, retrospective cohort study aiming to evaluate the effectiveness and safety of vedolizumab (VDZ) and infliximab (IFX) in biologic‐naïve patients with moderate‐to‐severe ulcerative colitis (UC). Methods: Biologic‐naïve patients with moderate‐to‐severe UC who were treated with IFX or VDZ for at least 14 weeks at three tertiary hospitals in southwest China between January 2021 and January 2023 were retrospectively included. Efficacy of the biologics was evaluated based on the steroid‐free clinical remission rate, clinical remission rate, and mucosal healing rate at Weeks 14 and 52. Adverse events related to biologic use were recorded. Results: Altogether 122 biologic‐naïve patients with moderate‐to‐severe UC were included. No marked differences in the steroid‐free clinical remission rate and clinical remission rate were observed between the two groups at Week 14 or Week 52 (P > 0.05). The VDZ group exhibited a higher mucosal healing rate at Week 14 compared to the IFX group (33.3% vs 16.9%, P = 0.036), while that at Week 52 did not differ between the two groups (65.6% vs 47.1%, P = 0.098). There was no statistically significant difference in the rate of adverse events between the two groups (P = 0.071). Conclusion: VDZ and IFX showed comparable clinical efficacy and safety profiles and can be used as viable first‐line therapeutic options for biologic‐naïve patients with moderate‐to‐severe UC. [ABSTRACT FROM AUTHOR]