There is increasing evidence in favor of the hypothesis that human tissue mast cells (MCs) are progeny of hemopoietic stem cells and are closely related to cells of the mononuclear phagocyte system. To test this hypothesis we investigated the immunoreactivity of normal/reactive MCs in 12 lymph node and tumor specimens and neoplastic MCs in 27 tissue samples from patients with various types of mastocytosis (urticaria pigmentosa, n = 13; cutaneous mastocytoma, n = 4; systemic mastocytosis, n = 6; and malignant mastocytosis, n = 4) with a panel of eight antibodies that stain macrophages or immune accessory cells and are reactive on routinely processed (paraffin-embedded, formalin-fixed) tissue. The MCs were stained by three of the macrophage-associated antibodies (namely, KP1 [CD68], Ki-M1P, and PG-M1 [CD68]), but were not stained by three other antibodies (namely, HAM56, MAC387, and LN5) or antibodies detecting immune accessory cells (DAKO-CD35 and anti-S-100 protein). While KP1 stained normal/reactive and neoplastic MCs in all the specimens investigated, Ki-M1P stained neoplastic MCs in nearly all the cases of mastocytosis but did not stain normal/reactive MCs. PG-M1 also failed to stain normal/reactive MCs and stained MCs in only approximately half of the specimens from cases of mastocytosis. Among these were most of the cases of systemic and malignant mastocytosis, but only a minority of the cases of cutaneous mastocytosis and a very few cases of urticaria pigmentosa. To summarize, (1) MCs display immunohistochemical staining properties resembling those of cells of the mononuclear phagocyte system but not those of macrophage derivatives belonging to the immune accessory cell compartment, and (2) PG-M1 and Ki-M1P are unique among the macrophage-associated antibodies investigated in that they do not stain normal/reactive MCs but exhibit preferential reactivity with the more atypical MCs in cases of systemic and malignant mastocytosis. © 1993.