Ligation of CD28 on T cells with its natural ligands B7-1 (CD80) or B7-2 (CD86) provides a major costimulatory signal for T cells and is of potential importance for tumor rejection. We previously reported a strong expression of B7-1 on Reed-Sternberg cells and anaplastic large cell lymphoma cells. We report here our findings on B7-2 expression by malignant lymphomas (n = 70). B7-2 was present on the neoplastic cells of anaplastic large cell lymphoma in two of three cases studied, and on a subpopulation of the malignant cells in one out of four cases of follicular lymphoma. B7-2 was not expressed by the neoplastic cells of the other non-Hodgkin's lymphomas (n = 32), including T cell-rich B cell lymphoma. In contrast, Reed-Sternberg cells in lymph nodes affected by Hodgkin's disease are strongly positive for B7-2 (n = 31). Evidence for a functional correlate of this expression was obtained by our findings that the combination of anti-B7-1 and anti-B7-2 monoclonal antibodies was more effective than each separately in blocking allogeneic T cell activation (proliferation and cytokine secretion) by Hodgkin's disease-derived cell lines as stimulators. The possible role of B7-1 and B7-2 expression for the course and symptomatology of Hodgkin's disease is discussed.