Chemoreceptors in the carotid bodies sense arterial oxygen tension and regulate respiration. Isolated carotid body glomus cells also sense glucose, and animal studies have shown the carotid bodies play a role in the counterregulatory response to hypoglycaemia. Thus, we hypothesized that glucose infusion rate would be augmented and neuro-hormonal counterregulation blunted during hypoglycaemia when the carotid bodies were desensitized by hyperoxia. Seven healthy adults (four male, three female) underwent two 180 min hyperinsulinaemic (2 mU (kg fat-free mass (FFM))(-1) min(-1)), hypoglycaemic (3.33 mmol l(-1)) clamps 1 week apart, randomized to either normoxia (arterial P(O2) (P(aO2)) 111 ± 6.3 mmHg) or hyperoxia (P(aO2) 345 ± 80.6 mmHg) (P < 0.05). Plasma glucose concentrations were similar during normoxia and hyperoxia at baseline (5.52 ± 0.15 vs. 5.55 ± 0.13 μmol ml(-1)) and during the clamp (3.4 ± 0.05 vs. 3.3 ± 0.05 μmol ml(-1)). The glucose infusion rate was 44.2 ± 3.5% higher (P < 0.01) during hyperoxia than normoxia at steady state during the clamp (28.2 ± 0.15 vs. 42.7 ± 0.65 μmol (kg FFM)(-1) min(-1); P < 0.01). Area under the curve values (expressed as percentage normoxia response) for counterregulatory hormones during hypoglycaemia were significantly suppressed by hyperoxia (noradrenaline 50.7 ± 5.2%, adrenaline 62.6 ± 3.3%, cortisol 63.2 ± 2.1%, growth hormone 53.1 ± 2.7%, glucagon 48.6 ± 2.1%, all P < 0.05 vs. normoxia). These data support the idea that the carotid bodies respond to glucose and play a role in the counterregulatory response to hypoglycaemia in humans.