The intravenous administration of E. coli endotoxin (2mg/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/100ml at 5h compared with 5.1 ±0.5mg/100ml pre‐endotoxin). Only one of eight animals so treated survived 8 h. 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. 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. Polymyxin B did not prevent the initial (1–3 h) and marked metabolic acidosis following endotoxin; however, after 3h, arterial lactate levels returned towards control whereas in the endotoxin‐alone group they continued to increase until death. 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.