Background: Despite significant advances in diagnosing and treating hemophagocytic lymphohistiocytosis (HLH) in the pediatric population, survival remains low and the extent of disease morbidity and health care utilization is poorly characterized. Thus, we sought to investigate morbidity, mortality, and the health care burden of HLH in a pediatric population. Methods: We queried the Pediatric Health Information System (PHIS) for children admitted with HLH and treated with etoposide and dexamethasone between 1/1/2004 – 9/30/2018. Collected data included demographics and clinical variables associated with morbidity and mortality. Results: A total of 493 patients (10.5 per 100,000 patients admitted) met inclusion criteria during the study period. The majority of patients (n = 284, 58%) were less than 5 years of age. A total of 331 patients were readmitted after the initial hospitalization, with 29% of readmissions complicated by infections. Median cost for initial hospitalization was $101,906 (IQR: $47,552 – $271,822). A significant number of patients required ICU care during both the initial admission (60%) and readmission (57%). Hematopoietic stem cell transplant (HSCT) was performed in 136 patients (28%) with a median time to HSCT of 126 days (IQR: 75-193 days). Overall mortality was 32% (n = 158), half occurring during the initial admission. There was a trend towards increased mortality in younger age groups. Median time to death during and after the initial admission was 45 days (IQR: 20-84 days) and 198 days (IQR: 108-368 days), respectively. Post-HSCT mortality rate was 35%. Conclusions: This represents the largest cohort of pediatric patients treated for HLH. Overall and post-HSCT mortality was consistent with prior publications. We observed significant morbidity and increased health care resource utilization in our cohort. These findings emphasize the need for novel therapeutic approaches to improve not only patient survival but also long-term quality of life. Planned future analysis of the PHIS data will be aimed at assessing treatment variability, morbidity and mortality depending on treatment, and risk factors associated with mortality in pediatric patients with HLH.