Objectives: We aimed to quantify the safety and effectiveness of vedolizumab (VDZ) when used for UC, and to identify predictors of response to treatment. Methods: Retrospective review (May 2014–December 2016) of VICTORY Consortium data. Adults with follow-up after starting VDZ for clinically active UC were included. Primary effectiveness outcomes were cumulative rates of clinical remission (resolution of all UC-related symptoms) and endoscopic remission (Mayo endoscopic sub-score 0). Key secondary effectiveness outcomes included cumulative rates of corticosteroid-free remission and deep remission (clinical remission and endoscopic remission). Cox proportional hazard analyses were used to identify independent predictors of treatment effectiveness. Non-response imputation (NRI) sensitivity analyses were performed for effectiveness outcomes. Key safety outcomes were rates of serious infection, serious adverse events, and colectomy. Results: We included 321 UC patients (71% prior TNFα antagonist exposure, median follow-up 10 months). The 12-month cumulative rates of clinical remission and endoscopic remission were 51% and 41%, respectively. Corresponding rates for corticosteroid-free remission and deep remission were 37% and 30%, respectively. Using NRI, 12-month rates were 20% (n = 64/321) for clinical remission, 17% (n = 35/203) for endoscopic remission, 15% (n = 30/195) for corticosteroid-free remission, and 14% (n = 28/203) for deep remission. A majority of the patients without adequate follow-up at 12 months who were deemed non-responders using NRI had already achieved clinical remission (n = 70) or a significant clinical response (n = 36) prior to 12 months. VDZ discontinuation prior to 12 months was observed in 91 patients, for lack of response (n = 56), need for surgery (n = 29), or adverse event (n = 6). On multivariable analyses, prior exposure to a TNFα antagonist was associated with a reduced probability of achieving clinical remission (HR 0.53, 95% CI 0.38–0.75) and endoscopic remission (HR 0.51, 95% CI 0.29–0.88). Serious adverse events and serious infections were reported in 6% and 4% of patients, respectively. Overall cumulative rates of colectomy over 12 months were 13%, with lower rates observed in patients naive to TNFα antagonist therapy (2%) than those who had been exposed to TNFα antagonists (19%). Conclusion: In this large real-world cohort we observed that VDZ was well tolerated and effective in achieving key clinical outcomes.