Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma resistant to conventional chemotherapy. The Bcl-2 pathway is deregulated in these tumors and may represent an interesting target for new therapeutic strategies. The new small-molecule pan–Bcl-2 inhibitor GX15-070 mimics BH3-only proteins by binding to multiple antiapoptotic Bcl-2 members. Here we show that GX15-070 induced apoptosis in vitro in MCL cell lines and primary cells from patients with MCL by releasing Bak from Mcl-1 and Bcl-X_L at short incubation times and low micromolar doses. GX15-070 was effective in cells bearing defective DNA damage-sensor genes or cell-cycle regulators, inducing Bax and Bak conformational changes, mitochondrial depolarization, phosphatidylserine exposure, and caspase-3 activation. Furthermore, GX15-070 synergized with bortezomib, sensitizing MCL cells to low doses of this proteasome inhibitor, by neutralizing bortezomib-induced Mcl-1 accumulation and cooperating with Noxa to induce Bak displacement from this protein. These events led to an increased activation of the mitochondrial apoptotic pathway. Importantly, GX15-070 alone or in combination with bortezomib showed no significant cytotoxic effect in peripheral blood mononuclear cells from healthy donors. All these findings suggest that GX15-070 alone or in combination with bortezomib represents a new attractive therapeutic approach for MCL treatment.