Oxygen (O₂) sensing by the carotid body and its chemosensory reflex is critical for homeostatic regulation of breathing and blood pressure. Humans and animals exhibit substantial interindividual variation in this chemosensory reflex response, with profound effects on cardiorespiratory functions. However, the underlying mechanisms are not known. Here, we report that inherent variations in carotid body O₂ sensing by carbon monoxide (CO)-sensitive hydrogen sulfide (H₂S) signaling contribute to reflex variation in three genetically distinct rat strains. Compared with Sprague-Dawley (SD) rats, Brown-Norway (BN) rats exhibit impaired carotid body O₂ sensing and develop pulmonary edema as a consequence of poor ventilatory adaptation to hypobaric hypoxia. Spontaneous Hypertensive (SH) rat carotid bodies display inherent hypersensitivity to hypoxia and develop hypertension. BN rat carotid bodies have naturally higher CO and lower H₂S levels than SD rat, whereas SH carotid bodies have reduced CO and greater H₂S generation. Higher CO levels in BN rats were associated with higher substrate affinity of the enzyme heme oxygenase 2, whereas SH rats present lower substrate affinity and, thus, reduced CO generation. Reducing CO levels in BN rat carotid bodies increased H₂S generation, restoring O₂ sensing and preventing hypoxia-induced pulmonary edema. Increasing CO levels in SH carotid bodies reduced H₂S generation, preventing hypersensitivity to hypoxia and controlling hypertension in SH rats.