Abstract: Multicentric Castleman's disease (MCD) is an indolent lymphoproliferative disorder. The pathogenesis of MCD has not been established, and its treatment remains uncertain. Several authors have described the relationship of human herpes virus type 8 (HHV-8) to MCD in human immunodeficiency virus (HIV)-positive patients. Recently, anti-CD20 monoclonal antibody (rituximab) is increasingly being used to treat HIV-positive MCD; although it is uncertain whether rituximab is effective for HIV-negative patients with MCD. To explore the benefit of rituximab for HIV-negative patients with MCD, we describe the clinical and biologic course in three HIV-negative patients with MCD, and examined the relationship of HHV-8 infection to HIV-negative MCD. Their polymerase chain reaction analyses for the HHV-8 sequence in peripheral blood were negative, and there was no relationship between HHV-8 infection and symptoms of HIV-negative MCD. Two of three patients (66%) achieved a near complete remission with no clinical symptoms due to MCD with a follow-up of 16–40 months after rituximab administration. One of the three patients presented no clinical remission of MCD after rituximab administration, although a significant decrease of inflammatory parameters was observed. These findings suggest that rituximab treatment may be an appropriate first-line therapy for HIV-negative MCD.