KCNQ2 channels have been detected in the rat node of Ranvier (Devaux et al., J Neuroscience, 24: 1236, 2004). To test whether KCNQ channels may mediate the slowly activating K⁺ current (I_Ks) voltage clamp experiments were performed in single large myelinated nerve fibres isolated from rat sciatic nerve. I_Ks was inhibited by the KCNQ blocker XE991 (IC₅₀ = 2.2 mM), linopirdine (IC₅₀ = 2.2 mM) and TEA (IC ₅₀ = 0.22 mM). The XE991-sensitive K⁺ current activated with a slow time course and did not inactivate; half-activation was at E_0.5 = -62 mV. The KCNQ channel opener retigabine (10 mM) activated I _Ks by shifting the activation curve to more negative membrane potentials (by -24 mV). In rats anesthetized with ketamine and xylazine, the nerves innervating the tail muscles were stimulated and compound action potentials were recorded. Injection of XE991 (2.5 mg/kg i.p.) eliminated all nerve excitability functions attributed to I_Ks, like accommodation to 100 ms subthreshold depolarizing currents. Also, the reduction in spike-frequency adaptation caused 100 ms suprathreshold currents to generate long trains of action potentials. Together, our data strongly suggest that I_Ks in large myelinated nerve fibres is mediated by KCNQ2 channels.