Dose response and tolerance to a small intravenous dose of Serratia marcescens lipopolysaccharide (LPS) were studied in awake sheep. Core temperature significantly increased after a dose of 0.002 micrograms/kg; changes in pulmonary arterial pressure, pulmonary vascular resistance, plasma thromboxane B2, and circulating leukocyte concentration occurred after 0.02 micrograms/kg; plasma 6-keto-prostaglandin F1 alpha increased after 0.2 micrograms/kg. Development of acute tolerance was studied by injection of S. marcescens LPS (0.02 micrograms/kg iv) on 3 consecutive days: pulmonary arterial pressure and thromboxane B2 levels were significantly lower than controls after the second dose, whereas fever and the degree of leukopenia were not diminished until the third dose. After intravenous administration of LPS given in increasing doses from 0.1 to 3.2 micrograms/kg three times weekly over 7 wk, there were no measurable changes in any of the above parameters after challenge with S. marcescens LPS (0.02 micrograms/kg) after a 1-wk rest period. In awake sheep, small intravenous doses of LPS can cause physiologically important changes of the pulmonary circulation and can alter the hemodynamic and eicosanoid mediator responses to subsequent challenges with LPS. Large intravenous doses of LPS can ablate the physiological responses to subsequent small doses of LPS.