BACKGROUND: Ustekinumab dose escalation (DE) may be an effective strategy to recapture clinical response in patients with ulcerative colitis (UC). The aim of this study was to assess the real-world long-term effectiveness and safety outcomes following ustekinumab DE in patients with moderate-to-severe UC. METHODS: This multicenter retrospective cohort study included patients with moderate-to-severe UC who received at least one IV induction ustekinumab dose between January 2016 and November 2021. We compared ustekinumab DE to no DE, examining clinical, biochemical, and endoscopic disease outcomes. The primary endpoint was corticosteroid-free clinical remission (partial Mayo score </= 2 without systemic corticosteroids) at the end of follow-up. Cox proportional hazards regression analysis was performed for factors associated with time to DE, and a Kaplan-Meier plot was created for visualizing drug persistence probabilities. RESULTS: We enrolled 121 patients. Eighty-one patients (67%) underwent DE during a median follow-up of 141 weeks. Corticosteroid-free clinical remission at the end of follow-up was achieved for 53.1% (DE group) and 57.5% (non-DE group). Discontinuation rates were 54.3% (DE group) versus 42.5% (non-DE group), mainly due to a lack of effectiveness. Two patients discontinued ustekinumab for adverse events. Ustekinumab persistence probability after 2 years was 40% (DE group) versus 79% (non-DE group). CONCLUSIONS: Our results indicate that DE is a commonly used method for optimizing ustekinumab treatment in moderate-to-severe UC. While DE appears safe, effectiveness and drug persistence beyond 2 years are limited.