To study interactions between hypoxemia and lung stretch in modulating ventilatory activity, an experimental preparation was used that allows independent control of static airway pressure (Paw) and arterial PO2 in anesthetized dogs. Phrenic burst frequency (f) and integrated amplitude (Phr) were monitored while Paw was varied between 2 and 12 cm H2O at levels of PaO2 between 30 and 200 mm Hg. Experiments were repeated in intact (n = 8) and carotid denervated dogs (CBX; n = 7). In intact dogs, f decreased with increasing Paw through an effect on the expiratory duration (TE). Hypoxia increased f by decreasing both the inspiratory duration (TI) and TE. Hypoxia had no effect on the slope of the f vs Paw relationship, but attenuated the effect of Paw on TE. Phr was increased by hypoxia, but Paw had little effect. After CBX, f was still inhibited by Paw, but PaO2 had no consistent effect on f, TI or TE at any level of Paw. Phr was inhibited by hypoxia after CBX, but Paw had no effect. The results indicate that Paw and PaO2 exert additive effects on f in anesthetized dogs. Hypoxia attenuates the effect of Paw on TE, which alone would attenuate the slope of the f vs Paw relationship. However, the effect of hypoxia on TI enhances the slope of the f vs Paw relationship, restoring a parallel shift. These effects are abolished by carotid denervation.