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A computer-based proportional-integral (PI) controller has been developed to control arterial oxygen levels in mechanically ventilated animals. Arterial oxygen saturation is monitored using a noninvasive oximeter and control is effected by adjusting the inspired oxygen fraction. The performance of the feedback system is sensitive to the open-loop gain so that the desired transient specifications can be achieved only by empirical adjustments of the PI controller. Because the open-loop gain includes the animal's response, it may vary with time and with the administration of positive end-expiratory pressure. Multiple-model adaptive control procedures were therefore used to desensitize the system to these variable gains. Computer simulations demonstrated the effectiveness of the algorithm over a wide variation of plant parameters. A comparison to a fixed, well-tuned proportional-integral controller showed an improvement in the regulatory response to a step disturbance. Animal experiments confirmed the feasibility of using multiple-model adaptive control to regulate arterial oxygen saturation.