This study examined the effects of human pregnancy on the central chemoreflex control of breathing. Subjects were two groups (n=11) of pregnant subjects (PG, gestational age, 36.5+/-0.4 wk) and nonpregnant control subjects (CG), equated for mean age, body height, prepregnant body mass, parity, and aerobic fitness. All subjects performed a hyperoxic CO2 rebreathing procedure, which includes prior hyperventilation and maintenance of iso-oxia. Resting blood gases and plasma progesterone and estradiol concentrations were measured. During rebreathing trials, end-tidal Pco2 increased, whereas end-tidal Po2 was maintained at a constant hyperoxic level. The point at which ventilation (Ve) began to rise as end-tidal Pco2 increased was identified as the central chemoreflex ventilatory recruitment threshold for CO2 (VRTco2). Ve levels below (basal Ve) and above (central chemoreflex sensitivity) the VRTco2 were determined. The VRTco2 was significantly lower in the PG vs. CG (40.5+/-0.8 vs. 45.8+/-1.6 Torr), and both basal Ve (14.8+/-1.1 vs. 9.3+/-1.6 l/min) and central chemoreflex sensitivity (5.07+/-0.74 vs. 3.16+/-0.29 l.min-1.Torr-1) were significantly higher in the PG vs. CG. Pooled data from the two groups showed significant correlations for resting arterial Pco2 with basal Ve, central chemoreflex sensitivity, and the VRTco2. The VRTco2 was also correlated with progesterone and estradiol concentrations. These data support the hypothesis that pregnancy decreases the threshold and increases the sensitivity of the central chemoreflex response to CO2. These changes may be due to the effects of gestational hormones on chemoreflex and/or nonchemoreflex drives to breathe.