The authors determined the phenotypes of neoplastic cells in true histiocytic lymphoma and malignant histiocytosis by using a large panel of monoclonal antibodies and enzyme histochemistry procedures. Although the phenotypes overlapped slightly, the authors noted a distinct pattern in these tumors. The tumor cells of malignant histiocytosis generally expressed the monocyte markers CD11b, CD11c, CD14, and CD45, especially after induction with phorbol ester. In contrast, the tumor cells of true histiocytic lymphoma exhibited a marker expression very similar to that of Reed-Sternberg cells in Hodgkin's disease. These cells expressed markers CD30, 2H9, and 1A2, but rarely expressed CD11b, CD11c, CD14, or CD45. Regardless of their cytologic features, the tumor cells from both types of histiocytic lymphoma exhibited diffuse nonspecific esterase and acid phosphatase activities, and they expressed histiocyte markers CD15, CD68, LN5, 1E9, and M387 to varying degrees. The tumor cells from both lymphomas did not exhibit T- or B-cell markers, T-cell receptor or immunoglobulin gene rearrangements, or gene translation products, even when they were induced with phorbol ester. The phenotypic expression in these two histiocytic malignancies suggests that they are derived from different types of histiocytes, or from histiocytes in different stages of maturation or differentiation, or from histiocytes that have distinct mechanisms of tumorigenic transformation. The expression of circulating monocyte markers in malignant histiocytosis suggests that this tumor originates in monocytes or free histiocytes, whereas the phenotype of true histiocytic lymphoma is compatible with an origin in fixed histiocytes, which generally are devoid of the monocyte markers CD11b and CD14.