Hemophagocytic lymphohistiocytosis (HLH) is an immune disorder characterized by cytokine dysregulation and uncontrolled activation of T lymphocytes and macrophages. It is categorized as primary when associated with specific genetic mutations or secondary when associated with infections, malignancies, or autoimmune disorders. Clinical features of HLH include unexplained fever, hepatosplenomegaly, pancytopenia, and severe hyperferritinemia. Treatment of primary HLH has become standardized based on the HLH-2004 protocol using cyclosporine, etoposide, and dexamethasone with or without intrathecal methotrexate followed by hematopoietic stem cell transplantation. Treatment of secondary HLH is directed at control of the underlying condition. If unsuccessful, cytotoxic agents such as those in HLH-2004, steroids, intravenous F-globulin, or targeted immune therapy have been used. Immunotherapy targeting CD52 expressed on immune effector cells of HLH is a rational therapeutic approach in patients too ill for traditional cytotoxic chemotherapy. We describe the successful use of alemtuzumab to treat HLH due to systemic lupus erythematosus.