Detection of abnormal numbers and/or distribution of bone marrow (BM) plasma cells (PCs) on trephine biopsies can be important in the differential diagnosis of multiple myeloma (MM) and other PC disorders. A variety of immunohistochemical markers can potentially improve the specificity and sensitivity of PC detection on routine histological sections obtained from trephine BM biopsies, but most of them are not completely satisfactory. In this study, we investigated whether the antibody CD138/B-B4, which is an optimal marker for PC detection on BM aspirates by flow cytometry, can be used successfully for the identification of PCs also on formalin-fixed, decalcified biopsies. A series of samples including normal BM , MM , monoclonal gammopathies of undetermined significance , and B-cell lymphoma of various types , including B-cell precursor lymphoblastic leukemia , lymphoplasmacytoid , immunoblastic , lymphocytic/CLL , hairy cell leukemia , large B-cell , mantle-cell , marginal zone  and follicular  lymphomas, have been investigated for CD138 expression using a sensitive immunohistochemical technique. Within the BM microenvironment, CD138 was characterized by excellent sensitivity and specificity. Virtually all normal and neoplastic PCs expressed clear-cut membrane CD138 immunostaining, whereas all other cell types did not. All cases of MM, including plasmablastic and leukemic cases, showed strong immunoreactivity. Conversely, all B-cell lymphomas, including all cases characterized by secretive features, lymphoplasmacytoid, and immunoblastic lymphomas, were completely negative. These results demonstrate that CD138 is a highly sensitive and specific marker that is useful for the rapid and precise localization of normal and neoplastic PCs on routine BM sections. In addition, because of its clear-cut cell membrane localization, CD138 can be used successfully in double-marker immunostaining reactions to evaluate precisely nuclear prognostic markers such as Ki67 and p53 in MMs.