Objective To investigate the clinical efficacy and safety of fosaprepitant in preventing nausea and vomiting caused by highly emetogenic chemotherapy (HEC) in children with cancer. Methods Pediatric cancer patients who received fosaprepitant to manage HEC-induced nausea and vomiting in the Department of Hematology and Oncology of Shanghai Children's Medical Center between July 2021 and November 2021 were enrolled into this study. The patients treated with fosaprepitant+ondansetron+dexamethasone were included in the fosaprepitant group, and the patients treated with ondansetron+dexamethasone were included in the control group. The clinical efficacy was evaluated by the difference of complete response (CCR, no vomiting/rescue medication) of acute, delayed and overall phase vomiting between the two groups. The safety assessment was carried out using the Common Terminology Criteria for Adverse Events v4.0 (National Cancer Institute). Results 107 patients were enrolled in this study (55 in the fosaprepitant group and 52 in the control group). There were 51 males and 56 females, with a median age of 3.5 (1.42-7.33) years. CCR rates were higher in the fosaprepitant group comparing that in the control group during the acute, delayed vomiting and overall phases, a lower proportion of children with mild and moderate vomiting, and no children with severe vomiting. Adverse reactions occurred in 25 cases (45.5%) in the fosaprepitant group, with a lower incidence rate than that in the control group (34 cases, 65.4%), and the difference was statistically significant (P<0.05). No severe adverse event was observed in this study. The difference in the incidence of headache, anorexia, malaise and other adverse reactions between the two groups of children was not statistically significant (P>0.05). Conclusion Fosaprepitant combined with ondansetron and dexamethasone is effective and safe in preventing related nausea and vomiting in children with cancer.