Peripheral chemoreceptors in the carotid body regulate respiration, sympathetic outflow, and blood pressure in response to hypoxia. The carotid bodies play a role in the counterregulatory response to hypoglycemia in animal models and may interact with the arterial baroreflex. We hypothesized that desensitization of the carotid bodies by hyperoxia in humans would blunt hypoglycemic counterregulation and baroreflex control of blood pressure during hypoglycemia. Seven healthy adults (age 26.7 ± 0.39, BMI 25 ± 0.32, M/4, F/3) each underwent two 180 min hyperinsulinemic (2 mU/kg FFM/min), hypoglycemic (3.33 mmol/L) clamps 1 week apart, randomized to either normoxia (arterial PO2 (PaO2) 111 ± 6.3 mmHg) or hyperoxia (PaO2 345 ± 80.6 mmHg) (p < 0.05). Plasma glucose concentrations were similar during normoxia and hyperoxia at baseline and during the clamp. The glucose infusion rate was 44.2 ± 3.5% higher (p < 0.01) during hyperoxia than normoxia during the clamp. Area under the curve values (expressed as % normoxia response) for counterregulatory hormones during hypoglycemia were significantly suppressed by hyperoxia. In addition, 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 CB were silenced. These data support the idea that the carotid bodies play a role in the counterregulatory response to hypoglycemia and in baroreflex control of blood pressure in humans.