M uscular exercise is associated with hypermetabolism and increased hypoxic ventilatory response (HVR). In order to dissociate mechanical and metabolic factors, the effect of hypermetabolism on hypoxic ventilatory response was evaluated at rest. Carbohydrate and protein feeding increases metabolic rate, and their effects on chemosensitivity, ventilation, and blood pH were evaluated in six normal subjects 2 h and 3 h after calorically equal test meals (1,000 cal).After carbohydrate, base-line oxygen consumption (V̇o₂) increased from 237±11.3 ml/min (SEM) to 302±19.4 (P < 0.001) and 303±18.5 (P < 0.001) at 2 h and 3 h, respectively. Hypoxic ventilatory response, measured as shape parameter A, increased from a control of 144±11.8 to 330±61.0 (P < 0.01) at 2 h and 286±57.0 (P < 0.05) at 3 h. These changes were associated with a mild metabolic acidosis as pH decreased from a control of 7.402±0.004 to 7.371±0.009 (P < 0.005) at 2 h and 7.377±0.008 (P < 0.005) at 3 h.After protein, V̇o₂ increased from 241±6.7 to 265±6.2 (P < 0.02) and 270±5.4 (P < 0.001), an overall increase less than that which occurred after carbohydrate (P < 0.01). Hypoxic ventilatory response increased from 105±14.5 to 198±24.3 (P < 0.02) at 2 h and 219±17.3 (P < 0.01) at 3 h, which was not different from the increase with carbohydrate. After protein, no acidosis occurred. Thus, after protein, HVR increased despite the absence of a systemic acidosis.We conclude that both carbohydrate and protein feedings are associated with resting hypermetabolism and increased HVR compared with the fasting state. For both meals, increased metabolic rate was correlated with increased hypoxic response.