Multinucleated giant cells resembling Reed-Sternberg (RS) cells are occasionally observed in high-grade lymphomas of the large-cell or immunoblastic type, but much less commonly in low-grade lymphomas. This study was conducted to determine whether RS-like cells found in seven B-cell low-grade lymphomas were immunologically similar to the neoplastic cells in the lymphoma or to the true RS cells seen in Hodgkin's disease, and whether they were therefore indicative of a composite lymphoma. Immunohistochemical studies were performed on paraffin sections of the seven low-grade (one small lymphocytic, one mantle zone, and five follicular) lymphomas with a panel of antibodies reactive with leukocyte common antigen (LCA), B-cell, T-cell, and Hodgkin's disease associated antigens. The RS-like cells were reactive with LCA (four of six), L26 (seven of seven), LN1 (five of six), LN2 (two of six), and MB2 (three of six). No positive staining was seen with either Leu-M1 or Ber-H2. The RS-like cells in the mantle zone lymphoma expressed L26, Leu-22, and kappa cytoplasmic light chains. This immunophenotype is similar to that of the neoplastic small lymphocytic cells. One of the low-grade follicular lymphomas progressed to an immunoblastic lymphoma with many RS-like cells. Paraffin immunohistochemistry on both lesions revealed a similar B-cell phenotype for the RS-like cells. Immunogenetic studies revealed B-cell and bcl-2 gene rearrangements in the immunoblastic lymphoma. These results indicate that RS-like cells in low-grade lymphomas are transformed neoplastic cells of B-cell lineage. With careful morphologic examination augmented by immunohistochemical studies, these lesions can be differentiated from Hodgkin's disease and from composite lymphomas of the combined Hodgkin's and non-Hodgkin's type.