We retrospectively reviewed 5 cases of hemophagocytic lymphohistiocytosis (HL) associated with human herpesvirus 8 (HHV-8) reactivation in human immunodeficiency virus (HIV)-infected patients. All patients had clinical and biological features characteristic of HL. Pulmonary symptoms were present in all patients and were frequently life threatening. The mean number of HL episodes was 6. Four patients had HL-associated Kaposi sarcoma, and 3 had multicentric Castleman disease. The mean CD4 cell count was 200 cells/mm(3). HIV loads were stable in all patients. All patients had high levels of HHV-8 in peripheral blood mononuclear cells during attacks, and a significant increase in this parameter before the attacks was seen in 3 patients. Although 2 patients died of HL, 3 are still alive and receiving etoposide therapy (mean follow-up, 3 years). HHV-8-related HL is associated with life-threatening symptoms and biological HHV-8 reactivation, and it may be controlled in the long term by etoposide therapy combined with highly active antiretroviral therapy.