Azathioprine (AZA) effectively prevents postoperative endoscopic recurrence (ER) in Crohn's disease (CD). However, the efficacy of AZA emerge needs 3 months. Exclusive enteral nutrition (EEN) can maintain remission for CD. The trial investigates whether AZA plus postoperative 3-month EEN is superior to AZA alone in preventing ER of CD.Totally, 84 high-risk CD patients undergoing intestinal resection received AZA alone or AZA plus a 3-month EEN (AZA+EEN) postoperatively. The primary endpoint was the rate of ER at month 12. Secondary endpoint included the rate of ER at month 3, clinical recurrence (CR), CD activity index (CDAI) scores, fecal calprotectin (FC) and CRP. Quality of life were assessed using Short Form-36 (SF-36) and the Inflammatory Bowel Disease Questionnaire (IBDQ).The patients in the AZA+EEN group exhibited significantly lower rates of ER compared to the AZA group at both months 12 (33.3% [13/39] vs 63.2% [24/38], P=0.009) and months 3 (8.6% [3/35] vs 28.1% [9/32], P=0.037) post-surgery. The rates of CR between the two groups at month-3 and month-12 were similar. The CDAI scores, FC, albumin level and CRP were all comparable between the 2 groups. The quality of life was significantly higher in the AZA group than that of the AZA+EEN group at month 3 but became comparable from month 5 to 12 postoperatively.In high-risk CD patients, combining AZA with postoperative 3-month EEN reduces 1-year ER but may temporarily impact quality of life. Further large-scale, long-term studies are warranted.© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.