Ventilation oscillates throughout a day in parallel with oscillations in metabolic rate. Histamine affects ventilation and the balance of the energy metabolism via H1 receptors in the brain. We tested the hypothesis that the ventilatory response to hypoxia varies between light and dark periods, and that histamine H1 receptors are required for the circadian variation, using wild-type (WT) and histamine H1 receptor-knockout (H1RKO) mice. Mice were exposed to hypoxic gas (7% O₂ + 3% CO₂ in N₂) during light and dark periods. Ventilation initially increased and then declined. In WT mice, minute ventilation (V_E) during hypoxia was higher in the dark period than in the light period, which was an upward shift along with the baseline ventilation. Hypoxia decreased the metabolic rate, while O₂ consumption (VO₂) and CO₂ excretion were higher in the dark period than in the light period. However, in H1RKO mice, changes in V_E during hypoxia between light and dark periods were minimal, because V_E was increased relative to VO₂, particularly in the light period. In H1RKO mice, the HCO₃- concentration and base excess values were increased in arterial blood, and the level of ketone bodies was increased in the serum, indicating that metabolic acidosis occurred. Respiratory compensation takes part in the V_E increase relative to VO₂ during hypoxia. These results suggested that changes in V_E during hypoxia vary between light and dark periods, and that H1 receptors play a role in circadian variation in V_E through controls of the acid-base status and metabolism in mice.