The role of hypermetabolism in the mediation of exercise hyperpnoea is contentious. Recent animal data has shown that the carotid body may be directly involved in establishing the hyperpnoea via a metabolic rate (MR)-induced elevation in the ventilatory sensitivity to CO₂ (Bin-Jaliah et al., 2005). A previous human study had also evidenced augmented chemosensitivity to CO₂ in response to raised MR, yet no inferences were made on the potential role that peripheral chemoreception could have played on these observations (Zwillich et al., 1977). Therefore we aimed to appraise the importance of peripheral chemoreception in the hypermetabolism-induced increases in chemosensitivity in awake humans. Fourteen healthy subjects took part in either one of two separate experiments. Local ethical approval was obtained and all subjects gave written informed consent. Each experiment involved a different methodology to assess the ventilatory response to euoxic (PetO₂ = 100mmHg) hypercapnia before and 210 minutes after the ingestion of a fixed amount of food; a five-minute ramp protocol (PetCO₂ = 0 to 8 mmHg above normal; n=7) in which peripheral chemoreception has been known to play an important role, and a step change protocol (PetCO₂ = 0, 2, 4, 6 and 8 mmHg above normal; each step lasting 3 minutes; n=7) in which the role of central chemoreceptors is predominant. MR was measured as oxygen consumption prior to each challenge of hypercapnia. Data were analysed by means of paired t-tests (SPSS 16.0) and significance was taken at p<0.05. All data are expressed as mean±S.E.M. MR was significantly increased by food ingestion in both experiments (‘Ramp’ experiment; 0.22±0.02 to 0.30±0.02; ‘Step’ experiment; 0.25±0.01 to 0.30±0.02, baseline vs 210 min, All P<0.03). The ventilatory sensitivity to CO₂, was increased significantly in the ramp protocol (1.13±0.11 to 1.78±0.15 L/min/mmHg, baseline vs 210 min, P=0.0001) but, although the mean was elevated, the sensitivity to CO₂ was not significantly increased in the step protocol (1.14±0.13 to 1.42±0.22 L/min/mmHg, baseline vs. 210min, P=0.26). Our results suggest that the hypermetabolism-induced increases in the ventilatory sensitivity to CO₂ might be primarily mediated through elevations in the peripheral chemoreceptor gain. Enhancement of this gain appeared to be facilitated even by mild increments of MR. The mechanism that couples metabolism to changes in chemosensitivity is not known.