Five cases of true histiocytic lymphoma (THL) were analysed by immunophenotyping and immunoglobulin/T-cell receptor genotyping. These cases showed striking morphologic diversity but a strong degree of immunophenotypic homogeneity. The malignant cells reacted with multiple histiocytic markers including CD11c (Ki-M1, LeuM5), CD14, CD68 (Ki-M6) and Ki-M8; anti-HLA-DR and non-specific esterase staining was also found in all cases. The malignant cells did not express monoclonal immunoglobulin and did not react with the B- or T-cell monoclonal antibodies used except for those known to be cytoplasmically expressed in monocytes/histiocytes, such as CD4 and CD19; B- and T-cell staining was otherwise limited to background small lymphocytes. By genotypic analysis, three cases showed rearrangements: one with T beta, one with T beta and immunoglobulin heavy chain (JH) and one with both JH and light chain; the remaining two cases retained their immunoglobulin and T-cell receptor genes in germline configuration. The results not only suggest that certain subsets of the histiocyte/reticulum cell system may be capable of rearranging immunoglobulin or T beta genes while simultaneously expressing multiple histiocytic surface antigens but also demonstrate the necessity of using multiple histiocytic-specific monoclonal antibodies and cytochemical staining in diagnosing THL. Gene rearrangement studies must be interpreted in conjunction with immunophenotyping and morphology in the determination of cell lineage.