Several recent reports have suggested that nodular lymphocyte predominance Hodgkin's disease (NLPHD) may be distinct from other forms of Hodgkin's disease and may be more closely related to B-cell non-Hodgkin's lymphoma. This is primarily based on immunophenotypic studies that have shown that the L & H cells in NLPHD demonstrate a B-cell phenotype. In 1989, Poppema reported that the T cells in NLPHD differ from T cells in other forms of Hodgkin's disease in that they demonstrate reactivity for Leu 7 (CD57). In this study we tested the hypothesis that Leu 7 (CD57) reactivity of small lymphocytes in NLPHD is an immunophenotypic feature that distinguishes NLPHD from nodular sclerosing Hodgkin's disease and from certain B-cell lymphomas that may histologically simulate NLPHD, namely T-cell-rich B-cell lymphoma and follicular lymphoma. Using an image analysis method, we found Leu 7 (CD57) reactivity in an average of 18.9% of the small lymphocytes in the nodules of NLPHD compared with 3.9% in nodular sclerosing Hodgkin's disease, 4.3% in T-cell-rich B-cell lymphoma, and 2.1% in follicular lymphoma. Moreover, Leu 7 (CD57)-reactive small lymphocytes often showed a distinctive pattern in NLPHD, forming a ring of cells around the large L & H cells. While scattered Leu 7 (CD57)-reactive lymphocytes were found in the other disorders, the percentage of reactive cells and the pattern of reactivity were significantly different in NLPHD. These results suggest that Leu 7 (CD57) reactivity may be used as an additional immunophenotypic criterion in distinguishing NLPHD from nodular sclerosing Hodgkin's disease, T-cell-rich B-cell lymphoma, and follicular lymphoma. The clinical and biological significance of Leu 7 (CD57) reactivity of small lymphocytes in NLPHD merits further investigation.