Central histaminergic neurons located in the posterior hypothalamus affect many autonomic behaviors. We examined the roles of these neurons in respiration in conscious histamine H1 receptor-knockout (H1RKO) and wild-type (WT) mice. Acute stepwise hypercapnia increased respiratory frequency (f), tidal volume (VT), and minute ventilation (VE) in both genotypes. However, H1RKO mice showed a lower f response and a higher VT response than those of WT mice. The VT-TI relation curve for H1RKO mice was shifted to the right and upward relative to that for WT mice, suggesting that in H1RKO mice the termination of inspiration is delayed by an increase in the inspiratory off switch (IOS) threshold. Increased body temperature increased the f response to hypercapnia in WT but not in H1RKO mice. This polypnea during hypercapnia was due mainly to a reduction in TE. These results suggest that central histaminergic neurons contribute to the termination of inspiration in the IOS mechanism and to polypnea during hyperthermia via activation of H1 receptors.