BACKGROUND AND OBJECTIVES: We explored the expression of LCK and BAFF-R (B-cell activating factor receptor) both of which are known to play a role in signaling and apoptosis, in routine tissue biopsies. It was hypothesized that their expression patterns might yield information on apoptosis as it occurs in normal and reactive lymphoid cells, and also be of value for the detection of lymphoma subtypes. DESIGN AND METHODS: Both molecules were studied in paraffin-embedded tissue sections and cell lines by immunoperoxidase staining, and were also studied by western blotting. Human tonsillar B-cell subsets were analyzed by flow cytometry for LCK expression. RESULTS: LCK was detected for the first time in germinal centers and, at lower levels, in mantle zone B cells. The presence of LCK in B cells was confirmed by western blotting. Cross-linking surface IgM reduced LCK expression whereas cross-linking surface CD40 appeared to have the opposite effect. BAFF-R was present on mantle zone B cells but absent or weakly expressed in germinal center cells. Most lymphomas of germinal center origin (e.g. follicular lymphoma) and also many mantle cell lymphomas, chronic lymphocytic leukemia (CLL) and most T-cell neoplasms expressed LCK. In contrast, BAFF-R was expressed in a variety of B-cell lymphomas, but often absent in grade 3 follicular lymphomas and diffuse large B-cell lymphomas (DLBCL). Both LCK-positive and BAFF-R-positive DLBCL tended to be of germinal-center phenotype. INTERPRETATION AND CONCLUSIONS: The reciprocal expression pattern of LCK and BAFF-R in germinal center and mantle zone B cells may reflect their opposing roles in apoptosis. Their detection in lymphoma tissue biopsies may therefore be of clinical relevance in predicting response to treatment.