Despite current therapy improvements for mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL), most MCL patients and ± 40% of the DLBCL patients experience relapses. Both MCL and DLBCL are aggressive B cell lymphomas, characterized with a higher proliferation rate. The anaphase promoting complex/cyclosome (APC/C) is an important checkpoint in mitosis, regulating the onset of the anaphase and cell cycle. This E3 ubiquitin ligase becomes activated upon interaction with the co-factor CDC20. CDC20 is frequently overexpressed in different human cancers (prostate cancer, breast cancer, multiple myeloma ...). This overexpression is associated with an aggressive course of the disease and a shorter overall survival. So far little is known about CDC20 in B cell lymphomas. Here, we investigated the inhibition of APC/C-CDC20 MCL and DLBCL. Using publicly available gene expression profiling data, we found that the majority of the DLBCL patients (>77%) exhibits a high CDC20 mRNA expression and that this overexpression is correlated with a worse prognosis, indicating that CDC20 is also involved in . Next, we evaluated the anti-lymphoma activity of the APC/C-CDC20 inhibitor proTAME (pT) using human MCL (Jeko-1, Mino and Rec-1) and DLBCL (OCI-Ly1, OCI-Ly7, SU-DHL-6, OCI-Ly3 and OCI-Ly10) cell lines. The pT treatment significantly increased the percentage of cells in metaphase. This metaphase arrest was accompanied by a strong reduction in MCL and DLBCL viability and a significantly increase in apoptosis. The induced apoptosis was found mediated by phosphorylation of the anti-apoptotic proteins Bcl-2/Bcl-XL, degradation/cleavage of the anti-apoptotic protein Mcl-1 and activation of the pro-apoptotic protein Bim. In addition, pT treatment induced phosphorylation of H2AX, suggesting that pT could also induce DNA damage. Finally, APC/C-CDC20 inhibition significantly enhanced the sensitivity of MCL and DLBCL cells the BH3 mimetic ABT-737 and ABT-199, as evidenced by a strong increase in caspase 3-dependent apoptosis compared to either agent alone. In conclusion, we identified APC/C-CDC20as a promising new target in the treatment of the aggressive B cell lymphomas MCL and DLBCL. In the future, the potential of specific CDC20 targeting, either alone or in combinations with currently available anti-cancer therapies, will continue to be investigated.