It is well-known that capsaicin activates TRPV1s existing in not only peripheral but also central terminals of primary-afferent fibers; the former activation results in inducing action potentials and the latter one leads to a barrage of the spontaneous release of L-glutamate from nerve terminals to spinal dorsal horn neurons. Although capsaicin is reported to produce a nerve conduction block, this action has not been thoroughly examined yet. We investigated the actions of capsaicin and its related substances on tetrodotoxin-sensitive and fast-conducting compound action potentials (CAPs) recorded from the frog sciatic nerve by use of the air-gap method. Capsaicin reversibly reduced the peak amplitude of CAP in a dose-dependent manner (by 40% at 200 μM). Although a TRPV1 antagonist capsazepine (50 μM) by itself inhibited CAPs, this drug did not affect the capsaicin-mediated inhibition of CAP. A TRPV1 agonist resiniferatoxin (5 μM) had no effect on CAPs. Like capsaicin, dihydrocapsaicin reduced the peak amplitude of CAP in a dose-dependent and reversible manner; this extent was almost comparable to that of capsaicin. Eugenol having the vanillyl group also inhibited CAPs, although this inhibition was less in extent than that of capsaicin. These results indicate that capsaicin inhibits CAPs without an activation of TRPV1s; a double bond existing in the chemical structure of capsaicin but not dihydrocapsaicin does not play a role in the CAP inhibition. [J Physiol Sci. 2008;58 Suppl:S78]