Background: the treatment of cancer is associated with nausea and vomiting, oral mucositis, constipation, xerostomia and diarrhea and weight loss, additionally; chemotherapeutic agents promote inflammatory changes in the gut, intestinal necrosis, and anaerobic conditions, allowing proliferation of Clostridium Difficile. Honey, as a natural honeybee product, has antioxidant, antimicrobial, immunomodulatory and anticancer effects. Honey can fight microbial infection by its immuno-activating, anti-inflammatory and prebiotic activity. Objectives: the aim of this study was to evaluate the effect of honey supplementation on frequency of Clostridium Difficile infection (CDI) and gastrointestinal complications in pediatric patients undergoing chemotherapy. Design: a cross sectional study conducted on 40 patients with malignancy recruited from Children's Hospital, Ain Shams University, Oncology Unit and Clinic, Cairo, Egypt in the period from December 2015 to December 2016. Patients were divided into two groups; group I (25 patients) received honey in the dose of 2gm/kg 3 times dailyfor 1month) while group II (15 patients) did not receive honey. All the studied patients were subjected to medical history and clinical examination, with special emphasis on gastrointestinal complication including oral mucositis, vomiting, diarrhea, constipation, and abdominal pain. Follow up was done for weight, height z score, gastrointestinal complications and any adverse events. Stool analysis, culture, C difficle toxin A, B by ELISA was done to all patients at baseline and repeated to patients receiving honey at week 4 of supplementation. Main outcome measure frequency of CDI, gastrointestinal complication, febrile neutropenia. Results: the frequency of C difficle was 8% (2), the first case was 9 years old patient with ALL (50%) and the other 11 years old patient with Burkitts lymphoma both were diagnosed by positive stool culture and positive stool ELISA for toxin A, B. gastrointestinal complications were significantly less and improved in the supplemented group and mean of hemoglobin significant increase in group 1. Conclusion: the frequency of CDI in children with cancer 8% diagnosed by stool culture and toxin A, B study in stool. Honey improved the oral mucositis and different GIT complications associated with chemotherapy.