BACKGROUND: In real-world clinical settings, the clinical efficacy of vedolizumab (VDZ) in patients with ulcerative colitis (UC) remains unclear. In this study, we aimed to evaluate the efficacy of prednisolone (PSL)-VDZ combination therapy in patients with UC. METHODS: Changes in the clinical activity index (CAI), blood test results, and the factors affecting VDZ rate and continuity were investigated. Patients who received at least 20 mg PSL within 1 week of VDZ induction were included in the VDZ + rapid PSL induction (VDZ + rPSL) group, and the remaining were assigned to the non-VDZ + rPSL group. Failure and non-failure in both groups were compared. RESULTS: We conducted a comparative analysis of 38 patients with UC treated with VDZ (VDZ + rPSL, n = 14; non-VDZ + rPSL, n = 24). The CAI in both groups improved significantly from week 2 to 24 compared with the pretreatment values (P < 0.01). Clinical remission and response at week 8 were significantly higher in the VDZ + rPSL group than in the non-VDZ + rPSL group (85.7% vs. 37.5%, P < 0.01 and 85.7% vs. 41.7%, P = 0.02, respectively). Kaplan-Meier analysis showed a significant difference in the failure-free rate between the two groups (log-rank test, P = 0.02). In the VDZ + rPSL group, only C-reactive protein (CRP) levels significantly improved in non-failure at week 2 (P=0.04). CONCLUSIONS: VDZ + rPSL induction therapy is beneficial for UC treatment. CRP levels 2 weeks after VDZ induction may influence the continuation rate in the VDZ + rPSL group.