The underlying mechanisms by which tumor cells are resistant to CTL-mediated apoptosis are not clear. Using a human model of B-cell non-Hodgkin's lymphoma (B-cell NHL), we show that intratumoral T_reg cells inhibit the proliferation and granule production of activated autologous infiltrating CD8⁺ T cells. Our results also show that degranulation and subsequent cytotoxic activity of infiltrating CD8⁺ T cells exposed to lymphoma B cells is completely attenuated by the presence of intratumoral T_reg cells. Furthermore, we show that increased numbers of intratumoral T_reg cells correlates with the number of CD8⁺ T cells in biopsy specimens from patients with B-cell NHL, supporting the in vitro findings that intratumoral T_reg cells inhibit proliferation of infiltrating CD8⁺ T cells. Taken together, these data indicate that human lymphoma B cells are sensitive to autologous CTL-mediated cell death but are protected by the inhibitory function of intratumoral T_reg cells. (Cancer Res 2006; 66(20): 10145-52)