The immunosurveillance of Hodgkin lymphoma (HL) by cytotoxic T lymphocytes (CTLs) is insufficient, and the clinical experience with adoptive transfer of CTLs is limited. We have previously reported that defects in mitochondrial apoptotic pathways and elevated XIAP expression confer resistance to different apoptotic stimuli in HL cells. Here, we aimed to develop molecular strategies to overcome the resistance of HL cells against CTL-mediated killing via granzyme B (grzB). In HL cells, grzB-induced mitochondrial release of proapoptotic Smac is blocked, which results in complete abrogation of cytotoxicity mediated by CTLs. Cytosolic expression of recombinant mature Smac enhanced caspase activity induced by grzB and restored the apoptotic response of HL cells. Similarly, down-regulation of XIAP by RNA interference markedly enhanced the susceptibility of HL cells for CTL-mediated cytotoxicity. XIAP gene knockdown sensitized HL cells for killing by antigen-specific CTLs redirected by grafting with a chimeric anti-CD30scFv-CD3zeta immunoreceptor. The results suggest that XIAP targeting by Smac agonists or XIAP-siRNA can be used as a synergistic strategy for cellular immunotherapy of Hodgkin lymphoma.