We conducted a retrospective study of the utility of Leu M1 monoclonal antibody staining of paraffin-embedded tissue in the differential diagnosis of Hodgkin's disease (HD). Forty-two cases of HD of various histologic types and 33 cases of non-HD lymphomas and hyperplasias were stained with Leu M1 using the avidin-biotin-peroxidase complex technique. Varying numbers, but not all Reed-Sternberg (RS) and Hodgkin's cells in all 42 cases of HD, were Leu M1 positive. These cases included seven examples of interfollicular HD and nine cases of lymphocyte-predominance HD, eight of which were nodular. Four of five cases of immunologically proved T-cell lymphoma contained Leu M1-positive RS-like cells, and Leu M1-positive RS-like cells were noted in two of five cases of non-HD lymphoma that were not phenotyped but were morphologically consistent with T-cell lymphoma. We concluded that Leu M1 staining is an aid in the diagnosis of HD, but it cannot be used to differentiate HD from T-cell lymphoma containing RS-like cells.