Objective To investigate the incidence of severe cancer therapy-related thrombocytopenia (CTRT) and associated factors in children. Methods A prospective observational study was conducted among 1 047 pediatric inpatients with cancer at Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicinefrom November 2023 to August 2024. Patients were divided into two groups based on the occurrence of severe CTRT. Multivariable logistic regression analysis was used to identify risk factors for severe CTRT. Results Severe CTRT occurred in 343 patients (32.76%). Multivariable logistic regression analysis showed that disease relapse, history of severe CTRT, nutritional risk, use of >3 antineoplastic agents, inclusion of platinum-based agents/cytarabine/anthracyclines in the regimen, and pre-treatment platelet count <100×10⁹/L were significantly associated with severe CTRT (P<0.05). Conclusions The incidence of severe CTRT in children is relatively high, and it is influenced by multiple factors including medical history (relapse, previous severe CTRT), treatment regimen (>3 antineoplastic agents, inclusion of platinum-based agents/cytarabine/anthracyclines), and health status (nutritional risk, pre-treatment platelet count <100×10⁹/L). High-risk children should be identified through comprehensive assessment of medical history, health condition, and treatment regimen to provide timely preventive and supportive care.