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Objective The viability of normal and malignant B-cells was shown to depend on the constitutive activation of the nuclear factor (NF)- κB pathway. Thus, attempts to find efficient inhibitors of NF-κB play a central role in the search for novel anti-B lymphoma therapies. We studied the effects of two NF-κB inhibitors, Bay 11-7085 (BAY) and caffeic acid phenethyl ester (CAPE), on the viability of B-lymphoma cell lines. Methods We investigated the mechanism(s) of the cytotoxic effect of the NF-κB inhibitors, BAY, and CAPE on human-lymphoma and nonhematological cell lines. Results BAY and CAPE were shown to kill Ramos-Burkitt's lymphoma cells with IC 50 values of 0.7 μM and 4 μM, respectively. The rapid killing by BAY (h) vs the slower killing by CAPE (1–3 days), and their differential effects on the stages of the cell cycle, indicated that these drugs induce killing by different mechanisms. BAY and CAPE induced a loss of the cytoplasmic compartment and generated pyknotic nuclei, which lacked nuclear or nucleosomal fragmentation, features characteristic of necrosis rather than apoptosis. BAY also induced a rapid loss of the mitochondrial potential and rapid inhibition of p65 NF-κB binding to its κB motif without reducing the level of nuclear p65. Conclusion Our results indicate that BAY causes a necrotic rather than apoptotic cell death, either through its effect on the NF-κB pathway and/or by affecting additional molecular targets. The high sensitivity of B-lymphoma cell lines to the cytotoxicity of BAY, justify further research to explore its potential therapeutic effect on human B lymphomas.