Histochemical and immunohistochemical studies have been reported in only a few cases of sinus histiocytosis with massive lymphadenopathy (SHML) to date. These indicate that SHML cells belong to the macrophage/histiocyte family, but their exact origin is still unknown. We determined the antigenic phenotype of SHML cells in sections from 20 cases of routinely fixed, paraffin-embedded tissue and from two cases of fresh frozen tissue using a broad panel of antibodies to macrophage/histocyte, B-, and T-cell antigens. SHML cells expressed the following: (1) S-100 protein, (2) "pan-macrophage" antigens such as EBM11, HAM 56, and Leu-M3, (3) antigens functionally associated with phagocytosis (Fc receptor for IgG, complement receptor 3), and lysosomal activity (lysozyme, alpha 1-antichymotrypsin, and alpha 1-antitrypsyn), (4) antigens associated with early inflammation (Mac-387, 27E10), (5) antigens commonly found on monocytes, but not tissue macrophages (OKM5, Leu-M1), and (6) "activation" antigens (Ki-1 and receptors for transferrin and interleukin 2). These data suggest that SHML cells are true functionally activated macrophages that may be recently derived from circulating monocytes.