HDACi block cancer cell proliferation by mechanisms that involve epigenetic gene regulation leading to cell growth arrest, differentiation, and apoptosis. Bortezomib inhibits NFKB signaling and induces apoptosis. Furthermore, anti-tumor activity of HDACi and bortezomib both depend in part on reactive oxygen species (ROS)-mediated pathways. Both have activity in NHL. We reasoned that these agents may be synergistic in part due to their dependence on overlapping pathways. We investigated the biology of PCI-24781, a pan-HDACi currently in clinical trials, and bortezomib both alone, and in combination, in HL (L428) and NHL cell lines (HF1, Ramos, & SUDHL4). Cells were incubated with increasing concentrations of PCI-24781 and bortezomib (0.25–2.0μM and 2.5–20nM, respectively) for 24–72 hour (hr). Apoptosis was determined by fluorescence-activated cell sorting (FACS) using AnnexinV-FITC/propidium iodide (AnnexinV + /PI + ) staining. Reactive oxygen species (ROS) were measured by oxidation of 2′7′dichlorofluorescein diacetate (H 2 DCFDA) to DCF and detected by FACS. Downstream targets of NFKB such as NFKB1, Myc and IL-8 were measured in Ramos using quantitative real time polymerase chain reaction (RT-PCR) following 24 hr incubation of cells with PCI-24781 and bortezomib alone, and in combination. Dose-dependent apoptosis was seen with PCI-24781 and bortezomib alone in all HL and NHL cell lines. IC70 (dose to achieve 70% AnnexinV + /PI + ) was 1μM for PCI-24781 and 2μM for L428. With bortezomib, the IC50 was 10nM in Ramos, HF1, and SUDHL4 and 20 nM in L428. The combination of PCI-24781 and bortezomib resulted in synergistic apoptosis (combination index