We reported a case of life-threatening hemophagocytic lymphohistiocytosis (HLH) treated with etoposide and anti-CD3 monoclonal antibody (OKT-3). A 3-year-old boy with fulminant HLH, characterized by CD3(+) CD56(-) atypical lymphocytosis and hemophagocytosis in peripheral blood and bone marrow, whose disease was refractory to conventional therapies including glucocorticoids, cyclosporine A, a small dose of etoposide and plasma exchange, was treated with a combination therapy of OKT-3 and etoposide. Analysis of mononuclear cells for clonality was performed. DNA derived from Epstein-Barr virus, herpes virus-6 and cytomegalovirus was also detected in mononuclear cells from the patient. The plasma cytokine levels were serially evaluated. By DNA analyses, monoclonal proliferation of T cells and a monoclonal population of cells containing the Epstein-Barr virus genome was demonstrated. With administration of two doses of 5 mg/m(2) of OKT-3 combined with 100 mg/m(2) of etoposide, atypical lymphocytes rapidly disappeared, and hematopoietic reconstitution was seen with disappearance of activated macrophages in the bone marrow 7 days after OKT-3 administration. Consistent overproduction of IL-10 through the clinical course was observed. Combined administration of OKT-3 with etoposide was effective in this patient. It seems appropriate to try this therapy for fulminant HLH refractory to conventional therapies.