PURPOSE: Smad proteins mediate cellular signaling through the transforming growth factor-beta family (TGF-beta s). Smads 2 and 3 transmit signals from TGF-beta, and Smad4 is a common mediator, as well. However, little is known concerning the expression patterns of Smads in lymphoid tissue. MATERIALS AND METHODS: Immunohistochemistry for Smad3 and Smad4 was performed on paraffin-embedded tissue sections collected from 26 T- or NK-cell lymphomas. RESULTS: Nearly all cells in germinal centers were positive for Smad3, and more than 50% of paracortical cells were positive for Smad3 in reactive lymphoid tissue. When Smad4 immunostaining was conducted, nearly all the cells in the germinal centers showed diffuse cytoplasmic staining, and most of them exhibited nuclear positivity, as well. In addition, more than 50% of the cells in the paracortex were positive for Smad4. Furthermore, the Smad3 staining pattern was preserved in all malignant lymphomas, but four of these cases (15%) exhibited decreased expression of Smad4. All lymphoblastic lymphomas showed strong positivity in most of tumor cells, but one unspecified peripheral lymphoma, two nasal NK/T cell lymphomas, and one anaplastic large cell lymphoma were negative for Smad4. CONCLUSIONS: These results suggest that TGF-beta-specific Smads may be actively involved in signal transduction in lymphoid organs and that Smad-mediated TGF-beta signaling pathways are operative in malignant lymphoma. In addition, loss of Smad4 expression might be associated with development of some T-cell lymphomas.