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Afferent loop syndrome (ALS) is a debilitating complication of recurrent gastric cancer. Surgical intervention is usually not feasible in the face of poor general performance, presence of advanced peritoneal carcinomatosis and limited survival of the patients. Non-surgical approaches include internal drainage by stenting at the stenotic or anastomotic site and external drainage via the percutaneous routes. Percutaneous transhepatic duodenal drainage (PTDD) has been shown to provide effective palliation for ALS, but long-term catheterization is usually inevitable. We hereby present two cases of recurrent gastric cancer whose ALS was successfully treated with PTDD followed by weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin (HDFL). PTDD rapidly ameliorated the incapacitating symptoms of ALS, and the effective, low-toxicity chemotherapy subsequently led to tumor regression, restoration of bowel patency and removal of the drainage tube. At present, both patients have remained ALS-free and drainage-free for 16 and 17 months, respectively. Our results indicate that this non-surgical approach with PTDD followed by weekly HDFL could serve as a safe and effective treatment for ALS in recurrent gastric cancer complicated by peritoneal carcinomatosis.