Voltage- and/or conformation-dependent association and dissociation of local anesthetic-class drugs from a putative receptor site in domain IV S6 of the sodium channel and slow conformation transitions of the drug-associated channel have been proposed as mechanisms of use- and frequency-dependent reduction in sodium current. To distinguish these possibilities, we have explored the reactivity to covalent modification by thiols and block of the mutations F1760C and F1760A at the putative receptor site of the cardiac sodium channel expressed as stable cell lines in HEK-293 cells. Both mutations decreased steady-state fast inactivation, shifting V1/2h from −86 ± 1.3 mV (WT) to −72.3 ± 1.4 mV (F1760C) and −67.7 ± 1 mV (F1760A). In the absence of drug, the F1760C mutant channel displayed use-dependent current reduction during pulse-train stimulation, and faster onset of slow inactivation. This mutant also retained some sensitivity to lidocaine. In contrast, the F1760A mutant showed no use-dependent current reduction or sensitivity to lidocaine. The covalent-modifying agent MTS-ET enhanced use-dependent current reduction of the F1760C mutant channel only. The use-dependent reduction in current of the covalently modified channel completely recovered with rest. Lidocaine produced no additional block during exposure to MTS-ET-treated cells (MTS-ET 43 ± 2.7%: MTS-ET lidocaine 47 ± 4.5%), implying interaction at a common binding site. The data suggest that use-dependent binding at the F1760 site results in enhanced slow inactivation rather than alteration of drug association and dissociation from that site and may be a general mechanism of action of sodium-channel blocking agents.