Abstract Background Postoperative recurrence (POR) in patients with Crohn’s disease (CD) can be prevented with early postoperative use of thiopurines or anti-TNFs. However, the benefit of medical prophylaxis has not been assessed in the long-term. We aimed to assess the risk of a second intestinal resection (surgical POR -sPOR-) for CD according to the use of early medical prevention of POR after a first resection. Methods Adult patients with CD who underwent a first ileocolic resection with ileocolic anastomosis between 2000 and 2020 and had at least one year of clinical follow-up, were identified from the Spanish ENEIDA registry. Medical prevention of POR was defined as any immunomodulator (IMM) or biological agent started within the first 3 months after the ileocolic resection and maintained for at least 3 months. Medical treatment of POR was defined as any IMM or biological agent started at least 6 months after the index surgery. Patients in whom ileocolic resection was due to cancer and those starting IMM or biologicals between 3-6 months, were excluded. sPOR was defined by a second intestinal resection at least 6 months after the first one. Results A total of 3,694 patients were included, of whom 2,274 (62%) started medical prevention (1,499 with IMM, 775 with biologicals). 45% exposed to IMM and 31% to biologicals before the first surgery. 30% had none, 43% had one and 27% more than one risk factor for POR. Perianal disease and penetrating behaviour were significantly more frequent among patients following prevention but active smoking at surgery was among non-prevention group. Median disease duration at first surgery of 42 months (IQR, 6-109) and median follow-up until second resection or last visit of 111 months (IQR, 63-168). Surgical POR occurred in 11% (8% prevention group vs 14% non-prevention group). SPOR-free survival was significantly higher among patients following medical prevention (P=.001). In the Cox regression analysis, medical prevention (HR 0.71, 95%CI 0.58-0.87; P=.001) was the only protective factor of sPOR, whereas having any risk factor (HR 1.58, 95%CI 1.23-2.01; P<.0001), L4 location (HR 1.99, 95%CI 1.62-2.45; P<.0001) and extraintestinal manifestations (HR 1.43, 95%CI 1.15-1.77; P=.001) increased the risk. Conclusion Postoperative medical prevention have additional benefits in the long-term by reducing the incidence of sPOR. Our findings support the use of medical prevention instead of endoscopy-driven strategies at least in patients with risk factors.