A model-based closed-loop control system is presented to regulate hypnosis with the volatile anesthetic isoflurane. Hypnosis is assessed by means of the bispectral index (BIS), a processed parameter derived from the electroencephalogram. Isoflurane is administered through a closed-circuit respiratory system. The model for control was identified on a population of 20 healthy volunteers. It consists of three parts: a model for the respiratory system, a pharmacokinetic model and a pharmacodynamic model to predict BIS at the effect compartment. A cascaded internal model controller is employed. The master controller compares the actual BIS and the reference value set by the anesthesiologist and provides expired isoflurane concentration references to the slave controller. The slave controller maneuvers the fresh gas anesthetic concentration entering the respiratory system. The controller is designed to adapt to different respiratory conditions. Anti-windup measures protect against performance degradation in the event of saturation of the input signal. Fault detection schemes in the controller cope with BIS and expired concentration measurement artifacts. The results of clinical studies on humans are presented.