Increasing evidence suggests that the secondary phase of sepsis (that is, after the first proinflammatory hours) is characterized by the occurrence of a systemic failure of the immune system. In the most immunodepressed patients, therapies could be used to restore normal immune functions. However, biomarkers need to be developed to beforehand specifically identify these patients. Of these biomarkers, diminished monocyte HLA-DR expression has rapidly become the most popular. Herein, novel perspectives regarding monocyte HLA-DR assessed as a dynamic parameter in septic patients will be discussed in the context of a recently published study investigating daily evolution of monocyte HLA-DR with regard to 28 day-mortality after severe sepsis.