We analyzed the combination of a proteasome inhibitor (bortezomib) with enzastaurin (PKC/AKT-inhibitor) or lenalidomide (immunomodulatory agent) for the inhibition of proliferation and induction of apoptosis in B-cell lymphoma cell lines and primary malignant cells. The effects of bortezomib, enzastaurin or lenalidomide, alone or in combinations, on cell viability and apoptosis were evaluated using the Cell Proliferation Kit and flow cytometry analysis. The interaction between drugs was examined by the Chou–Talalay method. Cell cycle analysis was performed by flow cytometry. The PI3K/AKT, PKC and MAPK/ERK signaling pathways were analyzed using western blot. Bortezomib with either enzastaurin or lenalidomide synergistically induced anti-proliferative and pro-apoptotic effects in B-cell lymphoma cells, even in the presence of the bone marrow microenvironment. The direct cytotoxicity is mediated by signaling events involving the PI3K/AKT, PKC and MAPK/ERK pathways leading to cell death. The significant increase of apoptosis was mediated by an increased ratio of pro-apoptotic proteins (Bax, Bad and Bim) to anti-apoptotic proteins (Bcl-2, Bcl-xL and Mcl-1), triggering the cleavage of caspases -3, -9, -8 and PARP. Further evaluation of the combination of bortezomib with enzastaurin or lenalidomide for the treatment of B-cell lymphoma is warranted, with the goal to improve the quality of life and survival of patients. Copyright © 2014 John Wiley & Sons, Ltd.