Immunohistochemical localization of S-100b protein and S-100ao protein in human lymphoreticular system was studied by using monospecific antibody directed against either the alpha subunit or beta subunit of S-100 protein. S-100b protein immunoreactivity was detected in Langerhans cells, interdigitating reticulum cells, and histiocytosis X cells, but not in ordinary macrophages and blood monocytes. In contrast, S-100ao protein immunoreactivity was detected in blood monocytes, macrophages of lymph node, alveolar macrophages of lung, and small numbers of Kupffer cells of liver. S-100ao immunoreactivity was also detected in epithelioid cells, Langhans giant cells, and foreign body giant cells. The present findings suggest that the presence of S-100ao protein in the cytoplasm is one of the characteristic features of cells in the human mononuclear phagocyte system. The detection of S-100b, but not S-100ao, immunoreactivity in Langerhans cells and interdigitating reticulum cells also suggests that they are independent of the monocyte-macrophage system. S-100ao protein may be a novel cytoplasmic marker for cells of the human monocyte-macrophage system.