Background: Hospitalized pediatric hematology-oncology patients have frequent clinical deterioration events (CDEs) requiring intensive care unit (ICU) interventions and resulting in high mortality, particularly in resource-limited settings. This study identifies independent risk factors for CDE mortality in hospitals providing childhood cancer care in Latin America and Spain. Methods: Centers implemented a prospective CDE registry, defined as unplanned transfer to a higher level of care, use of ICU-level interventions on the ward, or nonpalliative ward death. The authors analyzed registry data from April 2017 to December 2022. The primary outcome was CDEs mortality, defined as death occurring during ICU admission, <24 hours of ICU discharge, or end of ward-based ICU interventions. Multilevel modeling identified event-, patient-, and hospital-level independent risk factors for CDE mortality. Results: Among 69 participating hospitals in 18 countries, 4134 CDEs were reported in 3319 pediatric hematology-oncology patients with an event mortality of 26.8% (1108 events). Of all CDEs, 33.7% used ICU interventions on the ward and 87.5% were transferred to a higher level of care. In multilevel modeling, significant independent risk factors for event mortality present at the start of deterioration included patient (disease relapse) and event (e.g., reason for hospital admission, use of ICU intervention on wards, abnormal lactate, platelets, or C-reactive protein, reason for deterioration, and number of organs with dysfunction); hospital factors were not significant predictors of mortality. Conclusions: Hospitalized pediatric hematology-oncology patients with CDE have high mortality with significant variability across centers. Mortality, however, is largely driven by modifiable event-level factors, demonstrating the need for targeted interventions to improve survival.