Purpose: This is a retrospective, observational study of patients with secondary hemophagocytic lymphohistiocytosis (sHLH). The study objectives are to evaluate the natural history of sHLH treated with available therapies, including characterization of demographics, treatment utilization, clinical response, and survival. A subset of data from this study will serve as the external, historical control arm for the registrational study, “A Phase 2/3, Open-label, Single-arm, Multicenter, Historical Control Study to Evaluate ELA026 in Participants with Secondary Hemophagocytic Lymphohistiocytosis (sHLH)” (NCT05416307), which is designed to evaluate the safety and efficacy of ELA026 in participants with treatment naí¯ve (TN) sHLH, particularly in lymphoma-associated HLH (LAHLH). Methods: Data will be collected from electronic medical records of hospitalized adult patients (≥18 years) from 2010 to 2025 with newly diagnosed sHLH at selected academic medical centers. Patients will be identified through applicable ICD-9 and/or ICD-10 codes or by ferritin >10,000 ng/mL and at least one sCD25 (soluble IL-2r) value. sHLH experts will adjudicate variables that require clinical interpretation, such as confirmation of the date of sHLH diagnosis, trigger, and clinical outcomes. The historical control arm will be identified patients from this natural history study that meet modified inclusion/exclusion criteria from the Phase 2/3 study. An independent adjudication committee blinded to clinical outcomes, will review eligible patients from each site for inclusion in the historical control arm. Results: The primary objectives of the study are to characterize demographics, treatment utilization, survival outcomes (including 8-week survival), and clinical responses for hospitalized, newly diagnosed sHLH patients and to select an external historical control arm to be used for analysis purposes within the Phase 2/3 study. Conclusion: This study will be conducted at multiple US sites, with the possibility of expanding to global institutions. The study is anticipated to start in 2025.