Background & aims - Few data are available on the effects of tumor necrosis factor (TNF) antagonist therapy for patients with internal fistulizing Crohn's disease (CD) and there is debate over the risk of abscess. We aimed to assess the long-term efficacy and safety of anti-TNF therapy for patients with internal fistulas.Methods - We performed a retrospective study of data collected from Groupe d'Etude Thérapeutique des Affections Inflammatoires Digestives trial, from January 1, 2000 through December 31, 2017. Our final analysis included 156 patients who began treatment with an anti-TNF agent for CD with internal fistula (83 men; median disease duration, 4.9 years). The primary endpoint was the onset of a major abdominal surgery. Secondary analysis included disappearance of the fistula tract during follow up and safety. The Kaplan-Meier method was used for statistical analysis.Results - After a median follow-up of 3.5 years, 68 patients (43.6%) underwent a major abdominal surgery. The cumulative probabilities for being surgery-free were 83%, 64%, and 51% at 1, 3, and 5 years, respectively. A concentration of C-reactive protein >18 mg/L, albumin concentration < 36 g/L, presence of an abscess at the diagnosis of fistula, and presence of a stricture were independently associated with the need for surgery. The cumulative probabilities of fistula healing, based on imaging analyses, were 15.4%, 32.3%, and 43.9% at 1, 3, and 5 years, respectively. Thirty-two patients (20.5%) developed an intestinal abscess and 4 patients died from malignancies (3 intestinal adenocarcinomas). One patient died from septic shock 3 months after initiation of anti-TNF therapy.Conclusions - In a retrospective analysis of data from a large clinical trial, we found that anti-TNF therapy delays or prevents surgery for almost half of patients with CD and luminal fistulas. However, anti-TNF therapy might increase risk for sepsis-related death or gastrointestinal malignancies.