Histiocytic necrotizing lymphadenitis (HNL) is a rare benign disorder characterized histologically by nodal lesions composed of histiocytes, lymphoid cells, and so-called plasmacytoid T cells/plasmacytoid monocytes, with associated karyorrhexis. It has been proposed that plasmacytoid monocytes represent immature myeloid and lymphoid (plasmacytoid) early-committed dendritic cells (DCs). Monoclonal antibodies are now available for the detection of myeloid (CD1c [BDCA-1]+) and plasmacytoid (CD303 [BDCA-2]+) dendritic cells. With an extensive panel of antibodies to immature and mature DCs and interferon-alpha (IFN-alpha), cryostat section studies of 6 cases of HNL revealed that the morphologically distinctive mononuclear cells in lesional areas consisted of 2 populations of immature DCs: myeloid DCs immunoreactive for CD1c with coexpression of myeloid antigens CD13 and CD33 and plasmacytoid DCs immunoreactive for CD303 and CD123. These cells were CD68+, strongly expressed the IFN-alpha inducible protein MxA, and were nonreactive for fascin, a mature DC marker.