Monophosphoryl lipid A (MPL) is a "nontoxic" derivative of lipid A. We hypothesized that, because of the structural similarity between MPL and the lipid A portion of lipopolysaccharide (a "toxic" moiety of endotoxin), hemodynamic events occurring during endotoxemia could be attenuated by administration of MPL. Lipopolysaccharide (LPS) from Salmonella minnesota wild type S and MPL from S. minnesota R595 were used for the study. Fifteen Sprague-Dawley rats were randomized to receive either (1) 0.50 mg LPS per 100 gm body weight intravenously, (2) 0.50 mg MPL per 100 gm body weight intravenously, or (3) 0.5 mg MPL per 100 gm body weight intravenously followed in 15 minutes by 0.50 mg LPS per 100 gm body weight intravenously. Arterial pressure, thermodilution cardiac output, and central venous oxygen saturation were measured before and 30 and 60 minutes after LPS administration. In LPS-treated animals, cardiac output decreased from 448 +/- 28 ml/kg/min to 336 +/- 15 ml/kg/min (p less than 0.02), and central venous oxygen saturation decreased from 71% +/- 1% to 62% +/- 2% (p less than 0.05). Mean arterial pressure decreased from 134 +/- 5 mm Hg to 90 +/- 6 mm Hg (p less than 0.01). In MPL-treated and MPL + LPS-treated animals, no significant changes were observed in cardiac output, central venous oxygen saturation, or arterial pressure. These data indicate that MPL is not associated with the adverse cardiovascular responses observed after LPS administration. Furthermore, administration of MPL blocks the development of acute circulatory failure during endotoxemia.