Endotoxemia decreases the dose requirement for anesthetics but no data are available for propofol. A rat model was used in which the influence of endotoxin administration on the pharmacokinetics and pharmacodynamics of propofol was investigated. Chronically instrumented rats were randomly allocated to either a control (n = 9) or an endotoxin (n = 9) group. Six hours after pretreatment with either endotoxin or its solvent, propofol was infused (150 mg x kg(-1) x h(-1)) until isoelectric periods of 5 s or longer were observed in the electroencephalogram. The changes observed in the electroencephalogram were quantified using aperiodic analysis and used as a surrogate measure of hypnosis. The righting reflex served as a clinical measure of hypnosis. The propofol dose needed to reach the electroencephalographic end point in the endotoxin-treated rats was reduced by almost 50% (p < 0.01). This could be attributed to a decrease in propofol clearance and in distribution volume related to the degree of physiologic and metabolic disturbances induced by endotoxin. To investigate changes in end organ sensitivity, the biphasic electroencephalographic effect versus effect-site concentration relationship was studied. This relationship was characterized by descriptors that showed an increased intrinsic efficacy of propofol in the endotoxin group. The effect-site concentration at the return of righting reflex was lower in the endotoxin group. Our study demonstrates that endotoxin-treated animals need a lower dose of propofol to reach the same degree of anesthetic effect which can mainly be attributed to changes in pharmacokinetics.