1 The intravenous administration of E. coli endotoxin (2 mg/kg) in cats anaesthetized with pentobarbitone resulted in an initial acute increase in right atrial pressure and a transient systemic hypotension. Later (from 1 h onwards) there was a progressive decrease in cardiac output, a reduced right atrial filling pressure, systemic hypotension and a profound metabolic acidosis (lactate of 30 +/- 1 mg/100 ml at 5 h compared with 5.1 +/- 0.5 mg/100 ml pre-endotoxin). Only one of eight animals so treated survived 8 h. 2 Polymyxin B sulphate, given intravenously (1 min before endotoxin) as a bolus injection (5 mg/kg) followed by a continuous intravenous infusion (additional 5 mg/kg given over a 30 min period) prevented the endotoxin-induced pulmonary (right atrial) hypertension but not the acute systemic hypotension. 3 Polymyxin B sulphate reduced the delayed haemodynamic effects of endotoxin (systemic hypotension, decrease in cardiac output); all the eight animals so treated survived 8 h compared with only 1/8 of the controls. 4 Polymyxin B did not prevent the initial (1-3 h) and marked metabolic acidosis following endotoxin; however, after 3 h, arterial lactate levels returned towards control whereas in the endotoxin-alone group they continued to increase until death. 5 The mechanism of this marked protective effect of the antibiotic and the possible clinical repercussions are discussed; the most likely explanation for the protection is in chemical combination with the lipid A moiety of the endotoxin.