Systemic hypoxia in mammals is sensed and transduced by the carotid body into increased action potential (AP) frequency on the sinus nerve resulting in increased ventilation. The mechanism of hypoxia transduction is not resolved, but previous work suggested that fast Na⁺ channels play an important role in determining the rate and timing of APs. We speculated that Na⁺ channel activity between APs, termed persistent Na⁺ current (I_NaP), is responsible for AP generation, and riluzole and phenytoin, which inhibit this current would impair organ function. Using whole-cell patch clamp recording of intact petrosal neurons with projections to the carotid body, we demonstrated that I_NaP is present in chemoreceptor afferent neurons and is inhibited by riluzole. Furthermore, discharge frequencies of single-unit, chemoreceptor activity, in vitro, during normoxia (PO₂150 mmHg) and during acute hypoxia (PO₂90 mmHg) were significantly reduced at riluzole concentrations at or above 5 µM, and phenytoin at 100 µM without significantly affecting nerve conduction time, AP magnitude (inferred from extracellular field) and AP duration. The effect of both drugs appeared solely post-synaptic since hypoxia-induced catecholamine release in the carotid body was not altered by either drug. The respiratory response of unanesthetized, unrestrained two-week old rats to acute hypoxia (12% FiO₂), which was measured with whole body plethysmography, was significantly reduced following treatment with riluzole (2 mg/kg, IP) and phenytoin (20 mg/kg, IP). We conclude that I_NaP is present in chemoreceptor afferent neurons and serves an important role in peripheral chemoreceptor function and, hence, the ventilatory response to hypoxia.