The authors produced metabolic acidemia acutely in human subjects awake, sedated with halothane (0.1 MAC), and anesthetized with halothane (1.0 MAC) by infusing L-arginine hydrochloride, 5–6 mmol ± kg−1, over 3 h. Ventilation was recorded at resting arterial hydrogen ion concentration ([H+]a) and at 2–4 isocapnic increments of [H+]a, in each case, while end-tidal oxygen tension (PETo,) was varied between >300 mmHg and 45 mmHg. Total increments of [H+]a in awake, sedated, and anesthetized subjects were 13 ± 4, 12 ± 2, and 12 ± 3 nmol ± I−1(means ± SD). In the awake state, metabolic acidemia increased ventilation (VI) in proportion to [H+]a. The magnitude of response increased with reduced PETo2, such that the response to acidemia and hypoxemia combined was synergistic. The Δ&OV0312;I/Δ[H+]a slopes at PETo2values of >300, 100–120, and 45 mmHg were 0.47 ± 0.27, 0.85 ± 0.24, and 3.01 ± 1.30 1 ± min−1· nmol−1· 1, respectively (means ± SD). Halothane sedation reduced the responses to added [H+]a determined at PETo2values of 100–120 and 45 mmHg, as well as the response to hypoxemia and to the interaction of acidemia and hypoxemia, each to less than half awake values. Halothane anesthesia further impaired the responses to [H+]a and virtually abolished the response to hypoxemia and to acidemia-hypoxemia interaction. A small residual response to added [H+]a during anesthesia could be accounted for by a slight concurrent increase of Paco2, leaving no response attributable to metabolic [H+]a itself. The lack of ventilatory response to metabolic [H+] during anesthesia, when a response to CO2was clearly present, suggests that the metabolic acid stimulus did not reach the medullary chemoreceptors. We conclude that halothane in humans markedly reduces the peripheral chemoreceptor-mediated responses to metabolic acidemia and to acidemia-hypoxemia interaction, in parallel with its previously described effect on the response to hypoxemia. During light halothane anesthesia, ventilation is virtually unaffected by either the acidity or the oxygen tension of the blood.