Objectives: Chemotherapy-induced nausea vomiting (CINV) is a troublesome side-effect of chemotherapy in pediatric patients undergoing Osteosarcoma treatment. The role of 5HT3 antagonists needs to be explored for the same. The study aims to evaluate the superiority of single-dose Palonosetron over Granisetron in pediatric patients undergoing moderate emetogenic therapy for osteosarcoma. Materials and Methods: In this double-blind, case-controlled, randomized study, pediatric patients were assessed for acute nausea and vomiting following moderate emetogenic chemotherapy for osteosarcoma. These children were assigned to group I (palonosetron) and group II (Granisetron) without other antiemetic prophylaxis. The primary objective variable was children’s segment with complete response during the acute phase of the first on-study chemotherapy cycle. Risk factors associated with the trial were analyzed. The patients were followed for the first 24 hours following chemotherapy. Results: A total number of 200 children were evaluated, and other factors which might alter the response were assessed into two groups. These 200 children underwent 604 blocks of chemotherapy. The complete responses (CR) were documented in 83% and 72% receiving palonosetron and Granisetron, respectively, during the acute phase. The only dexamethasone, used as rescue medication, was found to be a significant risk factor that predisposed the response (p<0.05) Conclusion: Palonosetron is an effective alternative to Granisetron as a single dose for preventing CINV in children receiving MEC for osteosarcoma.