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Purpose: We recently developed a fully human monoclonal antibody (5F11) directed against the CD30 receptor, which is an excellent target for antibody based immunotherapy of malignant lymphoma cells. The antibody is cytotoxic for lymphoma cells in vitro and in vivo, however a partial or even complete resistance of several Hodgkin cell lines has been observed. In this study we analysed, whether the efficacy of 5F11 can be improved by combination with bortezomib. Methods and Results: Bortezomib is an inhibitor of the ubiquitin-proteasomes pathway that is toxic to multiple solid and hemotologic tumor cells. Using XTT viability assays, TUNEL assays and Facs analysis we demonstrate a synergistic toxic effect of 5F11 and bortezomib on the Hodgkin cell lines tested (L540, L1236, L428) and the CD30 expressing ALCL Karpas299. Moreover the growth of subcutaneous L540 derived tumors in SCID mice is inhibited by 5F11 in combination with bortezomib. The synergy depends on the regime of the drugs and is only seen when a pre-incubation with the antibody is followed by exposure to bortezomib. Immunofluorescence analysis demonstrates that the sensitization of the tumor cells correlates with a 5F11 dependent localisation of the survival factor NF-kB into the cell nuclei. A transfected NF-kB responsive reporter gene is 2–3 fold activated in 5F11 treated L428 cells and enhanced NF-kB binding is detected performing EMSA.. We furthermore measured an increased expression of the NF-kB target gene c-flip, that is down regulated after additional incubation of the tumor cells with bortezomib. Conclusion: Our data indicate that initial activation of NF-kB and downstream anti-apoptotic proteins in response to 5F11 via CD30 sensitizes the tumor cells to bortezomib induced cell death. The in vitro and in vivo activity of the combination of 5F11 and bortezomib suggests a therapeutic value for the treatment of HD patients.