Hypoglycemia impacts baroreflex control of blood pressure and cardio-vagal tone. The carotid bodies are sensitive to low glucose and mediate hypoglycemic counterregulation. Peripheral chemoreceptors in the carotid body also regulate respiration, sympathetic outflow, and blood pressure by serving as multi-modal physiological sensors. We hypothesized that desensitization of the carotid bodies by hyperoxia during hypoglycemia would blunt baroreflex control of blood pressure and cardio-vagal tone. Ten young healthy adults were exposed to normoxia [PaO2 122 ± 3 mmHg] or hyperoxia [PaO2 424 ± 39] (to blunt cellular activation of the carotid body glomus cells) during a hyperinsulinemic-hypoglycemic clamp (2 mU/kg FFM/min; 3.33 mmol/L). Two 180 min hyperinsulinemic-hypoglycemic clamps were performed on each subject one week apart, randomized to either normoxia or hyperoxia (p<0.05). Blood pressure was monitored continuously via a brachial arterial catheter. Cardio-vagal tone was assessed via the high frequency (HF) component of heart rate variability from 5 min periods of 5-lead ECG recording under baseline (euglycemia) and hypoglycemia. Mean blood pressure during hypoglycemia was significantly lower with hyperoxia than with normoxia (delta reduction from baseline: -5.4 ± 3.4 mmHg normoxia vs. -13.8 ± 1.9 mmHg hyperoxia, p<0.05). The typical baroreflex-mediated rise in heart rate and sympathetic activity with lower blood pressure did not occur when the carotid bodies were silenced. Area under the curve values (expressed as % normoxia response) for catecholamines during hypoglycemia were significantly suppressed by hyperoxia (norepinephrine -50.7 ± 5.2%, epinephrine -62.6 ± 3.3%, p<0.05 vs normoxia). HF values decreased significantly from baseline during hypoglycemia, however this reduction was attenuated under hyperoxia (Normoxia: -69% vs. Hyperoxia: -41%, p=0.04). Heart rate increased significantly during hypoglycemia (Normoxia: 59.7 bpm ± 2.4 vs. 71.9 ± 4.0; Hyperoxia: 60.6 bpm ± 1.9 vs. 68.5 ± 3, p<0.001), however, this increase was not different between normoxia and hyperoxia despite differences in cardio-vagal tone, heart rate variability, and blood pressure. These data indicate that the carotid body chemoreceptors may be partially responsible for the reduction in cardio-vagal tone associated with hypoglycemia, and they provide evidence for a role of the carotid body chemoreceptors in parasympathetic tone to the heart and sympathetic mediation of the baroreflex. Together, these data support the idea that the carotid bodies play a role in heart rate variability and baroreflex control of blood pressure in humans.