Background: Chronic pouchitis with penetrating anal lesions often leads to pouch failure after restorative proctocolectomy. The aim of this study was to analyze those predictors and to evaluate the effects of infliximab (IFX). Methods: We reviewed patients' backgrounds and performed a prospective trial of IFX treatment. Possible pre-operative factors were analyzed. Efficacy was assessed by comparing the pouchitis disease activity index (PDAI) and peri-anal DAI. Long-term efficacy was assessed via the rate of pouch failure. Results: A total of 41 patients with refractory pouchitis were included. Although the patients with penetrating lesions were younger than those without, neither predictive pre-operative factors nor a correlation of C-related protein levels were observed. A total of 10 patients with penetrating lesions were enrolled for IFX treatment. Although the PDAI and peri-anal DAI decreased significantly (p = 0.04 and p = 0.02, respectively), the primary non-responders during the induction of IFX were 3 patients with obvious abscesses. The 1-year cumulative pouch failure rate was 0% in patients without abscesses and 50% in patients with abscesses under IFX maintenance. Conclusions: IFX treatment for refractory pouchitis with penetrating complications appears to be effective. However, once penetrating lesions develop to abscesses, these lesions are difficult to heal.