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Postoperative recurrence (PR) occurs early after intestinal resection in >75% of Crohn's disease (CD) patients. No well-established strategy for long-term PR prevention is available. The aim was to prospectively evaluate the long-term endoscopic and clinical outcomes of postoperative CD on maintenance treatment with azathioprine (AZA), especially in patients who developed endoscopic lesions confined to the ileocolic anastomosis.Long-term AZA therapy (2–2.5 mg/kg/day) was initiated immediately after surgery in 56 consecutive patients who underwent a curative intestinal resection. Clinical and biological assessments every 3 months, as well as yearly endoscopic evaluation, were performed until the end of the study or clinical PR (CPR).Thirty-seven patients (70%) showed mucosal lesions at endoscopy after a median of 12 months (range 12–60); however, in 15 of these patients lesions were confined to the anastomosis and only 6 showed endoscopic progression, but none of them developed CPR. Among the remaining 22 patients with endoscopic PR (EPR), 23% suffered a CPR during follow-up. Thirty percent of patients remained free of EPR after a median follow-up of 33 months (range 12–84). The cumulative probability of EPR was 44%, 53%, 69%, and 82%, at 1, 2, 3, and 5 years, respectively. No predictive factors of EPR were found.Early postoperative use of AZA seems to delay EPR development in comparison to historical series or placebo groups in randomized controlled trials. Although usually considered as endoscopic recurrence, those lesions confined to the ileocolonic anastomosis are not likely to progress or to become symptomatic in the short term.