Flecainide belonging to class IC antiarrhythmics was shown to improve myotonia caused by sodium channel mutations in situations where the class IB antiarrhythmic drug mexiletine was less efficient. Yet little is known about molecular interactions between flecainide and human skeletal muscle sodium (hNav1.4) channels. Whole-cell sodium currents (INa) were recorded in tsA201 cells expressing wild-type (WT) and mutant hNav1.4 channels (R1448C, paramyotonia congenita; G1306E, potassium-aggravated myotonia). At a holding potential (hp) of -120 mV, flecainide use-dependently blocked WT and G1306E INa equally but was more potent on R1448C channels. For WT, the extent of block depended on holding voltage more negative than the activation threshold, being greater at -90 mV as compared to -120 and -180 mV. This behaviour was exacerbated by the R1448C mutation since block at -120 mV was greater than that at -180 mV. Thus flecainide can bind to inactivated sodium channels in absence of channel opening. Nevertheless, all the channels showed the same closed- state affinity constant (KR ~ 480 µM) and the same inactivated-state affinity constant (KI ~ 18 µM). Simulations according to the modulated receptor hypothesis mimic the voltage-dependent block of WT and mutant channels by flecainide and mexiletine. All the results suggest similar blocking mechanisms for the two drugs. Yet, since flecainide exerts use-dependent block at lower frequency than mexiletine, it may exhibit greater benefit in all myotonic syndromes. Moreover, flecainide blocks hNav1.4 channel mutants with rightward shift of availability voltage-dependence more specifically than mexiletine, owing to a lower KR/KI ratio. This study offers a pharmacogenetic strategy to better address treatment in individual myotonic patients.