Immunohistochemical localization of human leukocyte common antigen (LCA), a major membrane glycoprotein restricted to leukocytes, was evaluated in paraffin sections of a wide variety of hematopoietic and nonhematopoietic tissues (294 specimens) with monoclonal antibodies (PD7/26 and 2B11). In nonneoplastic tissues, LCA was identified on B and T lymphocytes, with variable immunoreactivities for plasma cells and histiocytes. By light microscopy and ultrastructurally, LCA was localized predominantly to the cell membrane and was also present focally in the cytoplasm. Myeloid cells at all stages of maturation were non-reactive, as were erythroid cells, megakaryocytes, and all non-hematopoietic tissues. Monocytes and mast cells, however, revealed membrane staining for LCA. In nearly all non-Hodgkin's lymphomas of the B- and T-cell types (74 of 80; 93 per cent), the lymphoid infiltrate was immunoreactive for LCA. In specimens from patients with Hodgkin's disease (nodular sclerosis and mixed cellularity type), rare Reed-Sternberg cells stained for LCA. Neoplastic cells were consistently immunoreactive for LCA in specimens from patients with chronic lymphocytic leukemia of the B- or T-cell type, prolymphocyte leukemia, and hairy cell leukemia. However, tissues from only three of eight cases of acute lymphoblastic leukemia were LCA-positive, with most non-reactive specimens exhibiting CALLA (J5) positivity. In cases of multiple myeloma, only minor populations of plasmacytic cells exhibited membrane staining for LCA. Nonhematopoietic neoplasms (102 evaluated), including small cell anaplastic carcinomas, amelanotic melanomas, alveolar rhabdomyosarcomas, Ewing's sarcoma, and germ cell tumors, were uniformly non-reactive. Human LCA represents an excellent cell marker for paraffin sections, to distinguish hematopoietic neoplasms, particularly of the lymphoid type, from poorly differentiated tumors of epithelial, mesenchymal, or neural derivation.