The effect of consciously controlled ventilation on the tolerable limits of the CO2 stimulus was systematically investigated in normal human subjects. Subjects maintained a fixed breathing regime while faco2 was slowly increased to the highest values that could be tolerated. By comparing the results of various breathing patterns, the independent effects of the components of the respiratory cycle could be deduced. Increases in mean lung volume (L.V.) and vt separately augmented tolerance of the chemical stimulus. Over a range, CÖ2 tolerance was directly proportional to f for a constant L.V. and vt, and different proportionalities obtained for different values of L.V. and vt. For wide variations in f and vt, CÖ2 tolerance was a single, linear function of ve. It is concluded that mechanoreflexes generated by the act of breathing inhibit the conscious perception of a chemical stimulus and, presumably, inhibit respiratory drive. Also, this negative feedback involves both adaptive and nonadaptive mechanisms. Results of experiments with resistive loading and with partial muscular paralysis by gallamine suggest that activation afferent discharge from spindles of respiratory muscles increases central inhibition. © 1968.