Background <p>Chronic pouchitis and Crohn’s-like disease of the pouch are frequent complications following restorative total proctocolectomy with ileal pouch–anal anastomosis (IPAA) for ulcerative colitis (UC). Biologics are increasingly used in refractory cases, but head-to-head comparative effectiveness data between biologic therapies are limited.</p> Aims <p>We aimed to compare week 52 clinical response and long-term treatment persistence among patients treated with vedolizumab, ustekinumab, or adalimumab.</p> Methods <p>This retrospective bi-center cohort study included adult patients with chronic pouchitis or Crohn’s-like disease of the pouch with mPDAI ≥ 5 at biologic initiation. The primary endpoint was week 52 clinical response based on cPDAI, defined as a ≥ 1-point reduction from baseline. Key secondary endpoints were treatment persistence and week 52 mPDAI response (≥ 2-point reduction). Additional secondary endpoints included cPDAI remission, mPDAI remission, ePDAI response and remission, and biochemical outcomes. Between-group comparisons were performed using chi-square tests for categorical variables and Kruskal–Wallis tests for continuous variables, with post hoc pairwise comparisons adjusted for multiple testing. Treatment persistence was analyzed using Kaplan–Meier survival curves with log-rank test.</p> Results <p>Seventy-seven patients were included (vedolizumab n = 36; ustekinumab n = 22; adalimumab n = 19). Baseline characteristics including distribution of chronic pouchitis and Crohn’s-like disease of the pouch were broadly comparable across groups, although ustekinumab was more frequently used as third-line therapy (p = 0.001). At week 52, cPDAI response occurred in 88.9% of patients treated with ustekinumab, 44.8% treated with vedolizumab, and 56.3% treated with adalimumab (p = 0.01). cPDAI remission was achieved in 33.3% of ustekinumab-treated patients, 13.8% of vedolizumab-treated patients, and 6.3% of adalimumab-treated patients (p = 0.09). No statistically significant differences were observed in biochemical remission across groups. Three-year treatment persistence was highest in the ustekinumab group (81.5%) compared with adalimumab (52%) and vedolizumab (35%) (p = 0.01).</p> Conclusions <p>In this real-world cohort, ustekinumab was associated with numerically higher long-term clinical response and treatment persistence compared with vedolizumab or adalimumab. These findings support the need for prospective trials to guide biologic selection in chronic pouchitis and Crohn’s-like disease of the pouch.</p>