Purpose Increasing evidence has shown an association of surgical technique, particularly anastomotic configuration, with postoperative recurrence of CD. This pilot study aimed to evaluate short-term outcomes of isoperistaltic side-to-side anastomosis (ISSA) employed on Crohn disease (CD) patients. Methods Data were retrieved from a prospectively maintained database. Postoperatively, all patients were followed up with close endoscopic (ileocolonoscopy) surveillance. Results From January 2017 to May 2021, 30 patients diagnosed with CD who underwent ISSA were compared with 45 CD patients who underwent antiperistaltic side-to-side anastomosis (ASSA). The 2 groups were comparable in baseline demographics and clinical characteristics. No significant differences were observed between groups regarding postoperative safety issues, including anastomotic leak, abdominal/pelvic abscess, length of hospital stay, readmission rate within 30 days, etc. At postoperative 24th month, reduced endoscopic recurrence was observed in the ISSA group compared with that in the ASSA group (18 of 24, 75.0%, vs. 36 of 38, 94.7%; P = 0.024). Regarding surgical recurrence, there was 0% in the ISSA group vs. 4.4% (2 of 45) in the ASSA group (P = 0.510). Conclusion In this study, we aimed to explore the influence of ISSA on postoperative recurrence in CD patients, and the preliminary results show that ISSA was technically safe and feasible, and appears to be effective in reducing postoperative recurrence in CD patients. However, our conclusion was underpowered due to small sample size and inadequate follow-up. We proposed ISSA be considered as another alternative option in the toolbox of inflammatory bowel disease surgeons when performing anastomosis on CD patients.