Using the Raji cell line as the immunogen source, we established stable murine hybridomas that secrete B-lymphocyte-specific monoclonal antibodies (MAbs). Two clones, designated EPB-1 and EPB-2, were selected for further study. Both EPB-1 and EPB-2 were typed by reaction with subclass-specific rabbit anti-mouse antibodies and were found to be IgG1 and IgG2a, with kappa-light chains, respectively. In radioimmunobinding and flow cytometric assays, EPB-1 and EPB-2 did not react with T-cell lines, nor with normal diploid cells. EPB-2, in contrast to EPB-1, did not react by flow cytometry with normal peripheral or bone marrow leukocytes. In normal lymphoid tissues, both antibodies were positive with germinal center and mantle zone B-lymphocytes. Additionally, EPB-1 also labeled interdigitating histiocytes in the T-cell zones. Both MAbs discriminated very well between lymphoid and nonlymphoid tissues; neither MAb cross-reacted with tested normal and solid tumor tissue specimens, or with cell lines of non-B-cell origin. Immunohistology also revealed that both MAbs stained malignant lymphoma tissue sections and cloned B-cell lymphomas, both in tissue culture and as human xenografts in nude mice. Due to the radiosensitivity of human lymphomas and the relative specificity of these two new MAbs, they appear to be potential radioimmunotherapeutic agents for human lymphoma.