The most recent definition of sepsis highlights the dysregulation of the host’s immune response to infection, which varies between individual hosts, with patients predominantly presenting with either hyperinflammation, immunoparalysis, or a combination of both states. Therefore, management strategies must be tailored to accommodate the heterogeneity of patients with sepsis, as these conditions are associated with distinct prognoses and therapeutic approaches. Identification of the immune response in patients with sepsis can be achieved through advanced techniques, such as gene expression profiling or, more simply, through a subphenotypic approach. This article introduces a subphenotypic classification of the sepsis immune response into macrophage activation-like syndrome (MALS), where pathological macrophage activation leads to excessive hyperinflammation, immunoparalysis, or neither. Patients are classified using serum ferritin levels and monocyte HLA-DR expression, which is assessed using peripheral blood. This classification demonstrates significant differences in survival across groups, which is attributed to their distinct underlying biological processes. Immunotherapeutic options also differ for these three groups. In the future, such immune response classifications will be valuable in sepsis management algorithms for personalized prognostication and therapy. © 2025, Indonesian Society of Internal Medicine. All rights reserved.