There is dispute regarding the necessity of infrapyloric lymph nodes dissection in right hemicolectomy for hepatic flexure colon cancer.To evaluate the risk factors for infrapyloric lymph nodes metastasis and prognostic role of infrapyloric lymph nodes dissection in patients with hepatic flexure colon cancer and identify the population who would benefit from infrapyloric lymph nodes dissection.Retrospective multi-center propensity score matching study to minimize heterogenity between 2 groups.This study was conducted at three medical centers.A total of 531 patients who underwent curative resection for hepatic flexure colon cancer were included.Logistic analysis was used to evaluate risk factors for infrapyloric lymph nodes metastasis and Kaplan-Meier analysis was used to evaluate overall survival.The metastasis rate of infrapyloric lymph nodes among patients undergoing infrapyloric lymph nodes dissection was 11.8% (26/221). Cox multivariate analysis confirmed that infrapyloric lymph nodes dissection was an independent prognostic factor after propensity score matching (hazard ratio 0.60, 95% CI, 0.38 to 0.84; p = 0.007). A proposed flow chart for infrapyloric lymph nodes dissection based on preoperative factors was created. Based on the proposed flow chart, patients with preoperative serum CEA level ≤5.0 ng/ml, cN+, and tumor size ≥5 cm, and patients with preoperative serum CEA level >5.0 ng/ml were defined as high-priority infrapyloric lymph nodes dissection group. The metastasis rate of infrapyloric lymph nodes in the high-priority group was 16.0% (20/125). In the high-priority group, patients undergoing infrapyloric lymph nodes dissection had better survival outcomes than those not undergoing infrapyloric lymph nodes dissection (p = 0.005).This study is limited by its retrospective nature.This study suggests that infrapyloric lymph nodes dissection should be performed in specific patients with hepatic flexure colon cancer. See Video Abstract.Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Colon and Rectal Surgeons.