A mathematical model consisting of six well-mixed tissue compartments was used for prediction of an anesthetic dose rate designed to maintain a constant arterial halothane concentration during closed-circuit anesthesia with halothane and nitrous oxide. Metabolism of anesthetics was not considered they were regarded as inert. Calculated rates of vapor were administered to provide a predicted level of anesthesia in 20 normal individuals during elective surgery. Arterial blood samples of these individuals were obtained periodically and analyzed for halothane to determine the relevance of the model to clinical anesthesia. The calculated dosage schedule was shown to predict clinical findings with acceptable accuracy in these patients. The assumption that arterial anesthetic concentration reflects instantaneous equilibration with cell receptors where anesthetics exert their effect in the brain was thus found to be justified by the clinical trial. In addition, we used the calculated anesthetic dosage schedule, which applies to a typical patient anesthetized under total-rebreathing conditions, as an input for an analog computer representing the six-compartment model, and we investigated effects of deviations between the predicted parameter values and actual clinical values of fat-to-muscle ratios and respiratory parameters upon the anesthetic levels obtained. The computer analysis suggests that respiratory factors such as lung shunts and dead space have little effect on patient response to closed-circuit anesthesia, in contrast to the effects observed in association with nonrebreathing techniques.