T-cell-rich B-cell lymphoma (TCRBCL), a variant of B-cell non-Hodgkin's lymphoma associated with an extensive nonneoplastic infiltrate of T cells, may be difficult to distinguish from other lymphoproliferative disorders, particularly when only limited biopsy specimens are available. The differential diagnosis usually includes lymphocyte predominance Hodgkin's disease (LPHD), which, although typically associated with nodular infiltrates, may exhibit a mixed nodular and diffuse or diffuse pattern of infiltration, with large neoplastic cells interspersed with small lymphocytes in a pattern that resembles TCRBCL. LPHD typically has a well-defined dendritic reticulum cell (DRC) network associated with the neoplastic infiltrate, but the presence of DRC in TCRBCL has not been well studied. To determine whether DRC staining is a useful marker to distinguish TCRBCL from LPHD, we examined formalin-fixed, paraffin-embedded tissue from lesions that fulfill the histologic and immunophenotypic criteria for TCRBCL for DRC staining with antibodies for CD21 and low-affinity nerve growth factor (LNGFR) receptor and compared this staining with that seen in typical cases of LPHD. As expected, 17 of 17 cases (100%) of LPHD exhibited DRC staining in an expanded follicular meshwork pattern. In contrast, none of the 15 cases of TCRBCL, including cases rich in histiocytes, exhibited DRC staining associated with the neoplastic infiltrate, except in residual, nonneoplastic germinal centers. We conclude that DRC staining is helpful for distinguishing TCRBCL from LPHD.