In this study, we investigated whether dendritic cells (DCs) are altered in classic Kaposi's sarcoma (cKS), a lympho-angioproliferative disorder associated with human herpesvirus-8 (HHV-8) infection. By direct analysis of peripheral blood DCs (PBDCs), we demonstrated that cKS patients have lower frequency of myeloid and plasmacytoid DCs than controls. This reduction was greater in patients with advanced stages of disease. PBDCs from cKS patients also showed up-regulated expression of the scavenger receptor CD91 and impaired IL-12 expression. PB monocytes that represent DC precursors in vivo and in vitro showed the same alterations; accordingly, DCs differentiated in vitro from cKS monocytes were similarly affected. The same alterations were induced by addition of cKS plasma during DC differentiation from control monocytes. These results indicate that PBDCs and their precursors are altered in cKS and suggest that soluble circulating factors participate in this process. The study may provide new insights into the pathogenesis of cKS.