Monophosphoryl lipid A (MPL) is a less toxic derivative of lipid A that enhances survival from endotoxemia. This study examined whether MPL induced resistance to Gram-positive sepsis and cytokines. Mice were administered MPL or saline (phosphate-buffered saline) and challenged 24 h later with live Staphylococcus aureus (SA), staphylococcus enterotoxin B (SEB), toxic shock syndrome toxin (TSST-1), and tumor necrosis factor (TNF). Survival was determined at 72 h. A separate set of animals was phlebotomized for determination of cytokines. MPL increased survival from S. aureus bacteremia from 20 to 87% (p < .05). Interleukin-6 (IL-6) and interleukin-1 (IL-1) and TNF were also significantly decreased. SEB and TSST survival were enhanced from 10 to 90% (p < .05). In SEB-treated animals, TNF and IL-6 levels were significantly decreased. Survival from TNF infusion was increased from 20 to 100% with MPL, however, no significant differences in cytokines were observed. These data suggest that MPL induces resistance to Gram-positive sepsis and cytokine-mediated activity.