The inhibitory role of TNF-alpha on survival of naïve and IL-2 treated NK cells has been demonstrated in the past. However, its effect on the function of these cells against tumor cells, in particular against oral tumors has not been established. We investigated the significance of secreted TNF-alpha in death and functional loss of splenocytes and NK cells in ex-vivo cultures with oral tumors. Oral tumors trigger potent secretion of TNF-alpha by human and murine immune effectors. Absence of TNF-alpha increases the cytotoxic activity and secretion of IFN-gamma by IL-2 treated splenocytes and NK cells in co-cultures with MOK L2D1+/p53-/- oral tumor cells. IL-2 treated splenocytes and NK cells from TNF-alpha -/- mice survive and proliferate more when compared to cells from TNF-alpha +/+ mice. Cell death induced by F. nucleatum, an oral bacteria, in TNF-alpha -/- splenocytes are considerably lower than that induced in TNF-alpha +/+ splenocytes where potent release of TNF-alpha is reproducibly observed. Addition of exogenous rTNF-alpha to IL-2 treated splenocytes and NK cells decreased survival and function of splenocytes and NK cells obtained from TNF-alpha -/- mice against oral tumors. These findings suggest that potent induction of TNF-alpha during interaction of immune effectors with oral tumors and/or oral bacteria is an important factor in decreasing the function and survival of cytotoxic immune effectors. Strategies to neutralize TNF-alpha may be beneficial in the treatment of oral cancers.