Inflammatory cytokines, including TNF-α, are produced by mononuclear leukocytes in response to numerous agents, such as microorganisms and microbial products, e.g., lipopolysaccharides (LPSs). We studied the modulation of LPS-induced release of TNF-α from human mononuclear cells by inositol hexaphosphate (IP6). This naturally occurring phytochemical, abundantly present in a regular diet, possesses several pharmacological activities beneficial for human health involving anticancer function and the ability to enhance the immune system. The present study on the effect of IP6 on the challenge of host defense system in cases of endotoxemia adds more to physiological importance of IP6 in terms of its immunomodulatory activity. Incubation of cells with IP6 alone (up to 250 μM) had no effect upon the basal secretion of TNF-α, whereas at higher doses it acted as an agonist by up-regulating the cytokine release. Incubation of cells with IP6 prior to LPS challenge resulted in differential effects which were dependent on triggering LPS. The response of cells to LPS from Desulfovibrio desulfuricans and Escherichia coli was diminished by IP6. Cell priming by IP6, resulting in up-regulation of TNF-α release was observed with Salmonella minnesota LPS stimulation. These results indicate that IP6 may exert immunoregulatory effects on mononuclear cell function and control their level of activation states.