Intrapulmonary chemoreceptors (IPC) are highly responsive respiratory chemoreceptors that innervate the lungs of birds and diapsid reptiles. IPC are stimulated by low PCO₂, inhibited by high PCO₂, and have vagal afferents that serve as a sensory limb for reflex adjustments of breathing depth and rate. Most IPC exhibit both phasic and tonic sensitivity to CO₂, and spike frequency adaptation (SFA) contributes to their phasic CO₂ responsiveness. To test whether CO₂-responsiveness and SFA in IPC is modulated by a Ca⁺⁺-linked mechanism, we quantified the role of transmembrane Ca⁺⁺ fluxes and Ca⁺⁺-related channels on single-unit IPC function in response to phasic changes in inspired CO₂. We found that (1) blockade of Ca⁺⁺ channels using cadmium or cobalt and blockade of L-type Ca⁺⁺ channels using nifedipine increased IPC discharge; (2) activation of L-type Ca⁺⁺ channels using Bay-K 8644 reduced IPC discharge; (3) blockade of Ca⁺⁺-activated potassium channels using charybdotoxin (antagonist of bK_Ca channels) increased IPC discharge, but neither charybdotoxin nor apamin affected SFA; and (4) blockade of chloride channels, including Ca⁺⁺-activated chloride channels (Cl_Ca), with niflumic acid decreased IPC discharge at low CO₂ and increased IPC discharge at high CO₂, resulting in a net attenuation of the IPC CO₂ response. We conclude that Ca⁺⁺ influx through L-type Ca⁺⁺ channels has an inhibitory effect on IPC afferent discharge and CO₂ sensitivity, that spike frequency adaptation is not due to apamin- or charybdotoxin-sensitive K_Ca channels in IPC, and that chloride channels blocked by niflumic acid help modulate IPC CO₂ responses.