The expression pattern of the BCL-6 transcription factor has been assessed in normal and neoplastic B-cell populations and in Hodgkin's disease. However, little is known about BCL-6 expression and its biological significance in T-cell neoplasms. In this study, a series of 59 lymphoma samples, including 27 CD30+ anaplastic large-cell lymphomas (ALCLs), 24 other peripheral T-cell neoplasms, and 8 T-cell lymphoblastic lymphomas (T-LBLs), as well as a panel of t(2;5)-positive lymphoma-derived human cell lines, were evaluated for BCL-6 protein expression by immunohistochemistry on frozen sections and cell smears. To define the relationship between BCL-6 protein and CD30 antigen in CD30+ ALCLs and in non-neoplastic lymph nodes, serial section immunohistochemistry and two-color staining were used in selected CD30+ ALCLs as well as in reactive lymph nodes with non-neoplastic T-cell proliferations. BCL-6 protein was expressed in 12 of 27 (45%) CD30+ ALCL cases, irrespective of their antigenic phenotypes (T-cell or null-cell type), and in the t(2;5)-positive cell lines. In contrast, the remaining 24 peripheral T-cell neoplasms as well as the 8 T-LBLs were considered negative for BCL-6 expression. Coexpression of CD30 and BCL-6, as detected in CD30+ ALCLs, was also found in a subset of non-neoplastic lymphoid elements, namely the large lymphoid cells scattered in the interfollicular areas of reactive lymph nodes. These findings suggest that CD30+ ALCLs may represent the neoplastic transformation of extrafollicular CD30+ cells and that BCL-6 may provide an additional marker for characterizing CD30+ ALCLs.