Activated B-cell type lymphoma (ABC), a subgroup of diffuse large B-cell lymphoma (DLBCL), has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the anti-apoptotic nuclear factor-κB (NFκB) pathway. The implication of NFκB inhibition in ABC has not yet been fully explored as a potential therapeutic target. Therefore, a panel of ABC cell lines was used to examine the effect of bortezomib, a proteasome inhibitor which blocks degradation of IκBα and consequently inhibits NFκB activity. Our data showed that bortezomib caused a dose-dependent growth inhibition and induction of apoptosis in all cell lines studied. We next determined the status of the NFκB pathway following bortezomib treatment and found that there was accumulation of IκBα without affecting its phosphorylation status at an early time point. Electrophoretic mobility shift assay showed that bortezomib treatment inhibited constitutive nuclear NFκB in ABC cell lines. Furthermore, treatment of ABC cell lines with bortezomib for 48 h also down-regulated the expression of NFκB-regulated gene products, such as IκBα, Bcl-2, Bcl-Xl, XIAP and survivin, leading to apoptosis via the mitochondrial apoptotic pathway. Altogether, these results suggest that NFκB may be a potential target for therapeutic intervention in DLBCL using proteasomal inhibitors such as bortezomib.