Platelet activating factor (PAF) amplifies the cytokine cascade in experimental models. This study was designed to investigate the role of PAF blockade during experimental Gram-positive shock by pretreatment with platelet activating factor-antagonist (PAF-A). Three groups of anesthetized rabbits were studied. Control animals received either saline or PAF-A only, and all survived, without hemodynamic changes. Animals in the second group received an infusion of Staphylococcus epidermidis, and all died in septic shock. Animals in the third group were pretreated with PAF-A and given the staphylococcal infusion; five of the six were alive at 200 minutes, with near-normal hemodynamics. The survival rate for animals pretreated with PAF-A was significantly higher than that for animals receiving staphylococci alone (P < .02). These results suggest that PAF is an important mediator of Gram-positive sepsis. Antagonism of PAF may be an effective potential therapy for sepsis.