Summary: Background: This observational real‐world evidence (RWE) study is based on prospectively collected data from the VEDOIBD registry study. Aim: To compare the effectiveness of vedolizumab and anti‐TNF agents in biologic‐naïve patients with ulcerative colitis (UC) at the end of induction and during maintenance treatment. Methods: Between 2017 and 2020, we enrolled 512 patients with UC starting therapy with vedolizumab or an anti‐TNF agent in 45 IBD centres across Germany. We excluded biologic‐experienced patients and those with missing partial Mayo (pMayo) outcomes; this resulted in a final sample of 314 (182 on vedolizumab and 132 on an anti‐TNF agent). The primary outcome was clinical remission measured using pMayo score; any switch to a different biologic agent was considered an outcome failure (modified ITT analysis). We used propensity score adjustment with inverse probability of treatment weighting to correct for confounding. Results: During induction therapy, clinical remission was relatively low and similar in vedolizumab‐ and anti‐TNF‐treated patients (23% vs. 30.4%, p = 0.204). However, clinical remission rates after two years were significantly higher for vedolizumab‐treated patients than those treated with an anti‐TNF agent (43.2% vs. 25.8%, p < 0.011). Among patients treated with vedolzumab, 29% switched to other biologics, versus 54% who had received an anti‐TNF agent. Conclusion: After two years of treatment, vedolizumab resulted in higher remission rates than anti‐TNF agents. [ABSTRACT FROM AUTHOR]