Propofol is a unique highly lipid-soluble anesthetic that is formulated in a fat emulsion (Diprivan) for intravenous (iv) use. It has the desirable properties of rapid onset and offset of effect following rapid iv administration and minimal accumulation on long-term administration. Based on physicochemical properties and preliminary brain solubility data, propofol should have an extended effect-site turnover and a resulting prolonged effect. However, a preliminary study in humans has reported a rapid blood–brain equilibration half-time (T1/2kE0) of only 2.9min. We used a chronically instrumented rat model to examine the unique disposition and electroencephalographic (EEG) pharmacodynamics of propofol. Although the pharmacokinetics were variable, there was low interindividual variability in the concentration–EEG effect relationship. The duration of EEG sleep was 26 (±44% CV) min following 11–15mg/kg doses of propofol. The T1/2kE0 was 1.7 (±32%) min. Apparent effect-site concentrations of 0.5–1 µg/mL were required to maintain sleep in rats. Like other general anesthetics, the concentration–EEG effect relationship of propofol is biphasic. At a propofol concentration of 0.6 (±35%) µg/mL, the number of EEG waves/s was maximal at 175% of baseline awake state. Further increases in the concentration of propofol depressed EEG activity until complete suppression occurred at 7 (±22%) µg/mL.