Mantle Cell Lymphoma (MCL) is a mature B-cell lymphoma with an aggressive course and generally poor prognosis. Conventional chemotherapy has little efficacy. Bortezomib (PS-341, Velcade (R)) is a novel, reversible and high specific proteasome inhibitor that appears as a new hope for MCL treatment. We have analyzed the in vitro sensitivity to bortezomib in four MCL cell lines and in primary tumor cells from ten MCL patients. Bortezomib induced phosphatidylserine exposure, mitochondrial depolarization, ROS generation, Bax and Bak conformational changes and caspase activation. In addition, ROS scavengers, but not pan-caspase inhibitors, blocked all apoptosis hallmarks. Protein and mRNA expression analysis, revealed marked upregulation of the BH3-only protein Noxa, between 4-6 h after bortezomib addition, independent of p53 status. However, this upregulation was faster and higher in cells with functional p53. Noxa RNA interference markedly decreased sensitivity to bortezomib, pointing this protein as a key mediator between proteasome inhibition and mitochondrial depolarization in MCL cells. Noxa interacts with the anti-apoptotic protein Mcl-1 and promotes Bak release from Mcl-1, suggesting that upregulation of Noxa might counteract Mcl-1 accumulation after bortezomib treatment. These findings should be useful to extend the therapeutic strategies in MCL patients and to improve their prognosis.