Osteoclasts are the sole bone-resorbing cells. Heightened activity of these cells under pathological conditions leads to the development of bone loss diseases, such as osteolysis, osteoporosis, and rheumatoid arthritis. We have shown previously that tumor necrosis factor α-(TNF) strongly induces osteoclastogenesis of preosteoclasts and do so through activation of the transcription factor, NF-κB. Most importantly, recent studies have shown that NF-κB is required for the development of osteoclasts. This transcription factor has also been proven as an essential mediator of inflammatory diseases including those related to bone. In this regard, we have shown that various mutated forms of IκBα are potent inhibitors of osteoclastogenesis. In this study, we examined the direct effect of DN-IκB on mature and preosteoclast development in the presence of TNF. Our findings indicate that once committed to the osteoclastogenic pathway, preosteoclasts form giant and hyperactive osteoclasts in response to TNF. However, administration of DN-IκB to cultures prior to TNF exposure averts the osteoclastogenic effect of TNF into apoptosis. Screening potential mediators of DN-IκB and TNF-induced apoptosis shows that caspase 3, caspase 9, poly-(ADP-ribose)polymerase, and Bax are activated, whereas levels of Bcl-XL, cIAP-1, and TRAF6 were reduced. Taken together, these findings suggest that under conditions of NF-κB inactivity levels of pro-survival factors are diminished, which in turn facilitates TNF induction of pro-apoptotic factors leading to apoptosis.