Cocaethylene, a metabolite of cocaine and alcohol, is a potent inhibitor of the cardiac (Na v 1.5) sodium channel heterologously expressed in Xenopus laevis oocytes. Cocaethylene produces minimal tonic block under resting conditions but causes a potent use-dependent inhibition during repetitive depolarization and a hyperpolarizing shift in the steady-state inactivation. The data are consistent with a state-dependent binding mechanism, which has high affinity for inactivated channels (K I ϭ 17 M) and low affinity for resting channels (K R ϭ 185 M). Mutations of the interdomain D3-D4 linker eliminated rapid inactivation and weakened the cocaethylene inhibition, consistent with an important role for fast inactivation in cocaethylene binding. A rapid component of cocaethylene inhibition was observed in a noninactivating mutant of Nav1.5 that was tightly linked to channel opening and displayed properties consistent with a pore blocking mechanism. Hyperpolarization caused the noninactivating mutant channel to close, trapping cocaethylene and slowing the recovery. Mutation of a conserved isoleucine (I1756C) located near the extracellular end of the D4S6 segment accelerated the recovery of the noninactivating channel, suggesting that this mutation facilitates cocaethylene untrapping, which seems to be the rate-limiting step in the recovery when the channel is closed. This contrasts with the rapidly inactivating channel, where the I1756C mutation did not alter the recovery from cocaethylene inhibition. The data suggest that additional mechanisms, such as more stable cocaethylene binding, may be a more important determinant of recovery kinetics when the channels are inactivated. The data indicate that deactivation and inactivation slow the recovery and potentiate the cocaethylene inhibition of the Nav1.5 channel by distinct mechanisms.