Acute exposure to hypoxia decreases insulin sensitivity in healthy adult humans; the mechanism is unclear, but increased activation of the sympathetic nervous system may be involved. We have investigated the hypothesis that short-term sympathetic inhibition attenuates hypoxia induced insulin resistance. Insulin sensitivity (via the hyperinsulinaemic euglycaemic clamp) was determined in 10 healthy men (age 23 ± 1 years, body mass index 24.2 ± 0.8 kg m⁻² (means ± SEM)), in a random order, during normoxia (FIO₂ =0.21), hypoxia (FIO₂ =0.11), normoxia and sympathetic inhibition (via 48 h transdermal administration of the centrally acting α2-adrenergic receptor agonist, clonidine), and hypoxia and sympathetic inhibition.Oxyhaemoglobin saturation (pulse oximetry) was decreased (P<0.001) with hypoxia (63 ± 2%) compared with normoxia (96 ± 0%), and was unaffected by sympathetic inhibition (P>0.25). The area under the noradrenaline curve (relative to the normoxia response) was increased with hypoxia (137 ± 13%; P =0.02); clonidine prevented the hypoxia induced increase (94 ± 14%; P =0.43). The glucose infusion rate (adjusted for fat free mass and circulating insulin concentration) required to maintain blood glucose concentration at 5 mmol l⁻¹ during administration of insulin was decreased in hypoxia compared with normoxia (225 ± 23 vs. 128 ± 30 nmol (kg fat free mass)⁻¹ pmol l⁻¹ min⁻¹; P =0.03), and unchanged during normoxia and sympathetic inhibition (219 ± 19; P =0.86) and hypoxia and sympathetic inhibition (169 ± 23; P =0.23). We conclude that short-term sympathetic inhibition attenuates hypoxia induced insulin resistance.