Vascular endothelial growth inhibitor (VEGI) is an endogenous inhibitor of endothelial cell growth and a promising candidate for cancer therapy. VEGI is able to inhibit tumor growth by specifically targeting the tumor neovasculature. Increasing the anti-angiogenic potential of this cytokine is of great interest for its therapeutic potential. NF-kappaB is known to have an integral role in TNF superfamily signaling, acting as a pro-survival factor. A role of VEGI-induced NF-kappaB activation in endothelial cells has yet to be described. Here we show that suppression of the NF-kappaB pathway can increase the apoptotic potential of VEGI. We used siRNA to deplete NF-kappaB or its activator IKK2 from adult bovine aortic endothelial cells. The siRNA treatments diminished VEGI-induced NF-kappaB activation, evidenced from a reduced extent of NF-kappaB nuclear translocation and diminished expression of NF-kappaB-target genes such as interleukins-6 and -1beta. The siRNA-treated endothelial cells when exposed to VEGI exhibited a marked decrease in cell viability and a significant increase in apoptosis. These results confirm that VEGI utilizes NF-kappaB as a pro-survival role factor in endothelial cells. We then examined whether a combination of VEGI with NF-kappaB inhibitors would constitute a more potential therapeutic regiment. We found that in the presence of the NF-kappaB inhibitors curcumin or BMS-345541 there was a marked increase in the apoptotic potential of VEGI on endothelial cells. These findings indicate that a combination therapy using VEGI and NF-kappaB inhibitors could be a potent approach for cancer treatment.