Abstract Background Prophylactic medication following ileocecal resection (ICR) is recommended in patients with Crohn’s disease (CD), particularly in patients at increased risk of recurrence. This study aimed to evaluate the effect of prophylactic medication on long-term prognosis. Methods A retrospective cohort study was performed in patients with CD who underwent a primary ICR. Patients were divided into two groups: prophylaxis (i.e. initiation of prophylactic medication<12 weeks following ICR) versus no prophylaxis. The primary and secondary outcomes were surgical recurrence and severe endoscopic recurrence (modified Rutgeerts score ≥ i3). To compare the outcomes between both groups, inverse propensity score-weighted comparison was used to adjust for confounding and selection bias. The survival and association between prophylaxis and both outcomes were assessed with Kaplan-Meier analyses and Cox proportional hazard models. Results 811 patients underwent an ICR median follow-up 5.8 years (IQR 2.5 – 10.7)(Table 1). Prophylaxis was initiated in 297/811 37% patients. In 364/514 71% patients without prophylaxis, medication was started after median follow-up 15 months IQR 7.2 – 46.5. Cumulative rates of surgical and endoscopic recurrence at 1, 2, 5 and 10 years were significantly lower in patients with prophylaxis versus no prophylaxis 1%, 3%, 9% and 19%, vs. 3%, 4%, 11% and 23%, p < 0.05 and 4%, 8%, 15% and 27% vs. 10%, 16%, 25% and 40%, p < 0.01. Propensity-scored weighted analysis showed that patients treated with prophylaxis were less likely to experience surgical recurrence aOR 0.52; 95% CI 0.33 – 0.82 and severe endoscopic recurrenceaOR 0.53; 95% CI 0.35 – 0.81. In multivariable analysis, prophylaxis was identified as protective factor for surgical aHR 0.67, 95% CI 0.45 – 0.99 and severe endoscopic recurrence aHR 0.54, 95% CI 0.37 – 0.78 (Table 2). Conclusion Surgical and severe endoscopic recurrence up to 10 years following primary ICR are significantly reduced in patients with CD who received prophylaxis as compared to no prophylaxis. Prophylaxis was associated with the prevention of surgical and severe endoscopic recurrence.