Orphenadrine is most often used against muscle spasm and rigidity, and pain of various etiologies. The drug may act on multiple targets, including muscarinic, histaminic, and NMDA receptors. Its structure recalls that of local anesthetics, with an aromatic hydrophobic moiety linked to a protonable tertiary ammine terminal. Thus we wondered whether orphenadrine may also block voltage-gated sodium channels. We tested the drug on whole-cell sodium currents recorded using patch-clamp in HEK293 cells expressing the skeletal muscle (Nav1.4), cardiac (Nav1.5) and neuronal (Nav1.1 and Nav1.7) subtypes of human sodium channels. The results indicate that orphenadrine inhibits sodium channels in a concentration, voltage and frequency dependent manner. Introducing the F1586C mutation in hNav1.4 reduced two-fold the tonic block at the holding potential (hp) of -120 mV and almost zeroed the use-dependent block at 10 Hz, indicating that orphenadrine binds to the same receptor as the local anesthetics. Channel state-dependent affinities of orphenadrine were calculated using specific protocols. At the hp of -180 mV, the entire population of channels are closed and ready to open in response to depolarization. Thus determination of tonic block at this hp allows the determination of drug affinity for resting channels, which was 160 μM. The affinity for inactivated sodium channels (KI) was calculated according to the modulated receptor hypothesis, which forecasts that the apparent affinity measured at a particular hp depends on the proportion of resting and inactivated channels at this hp. The calculated KI value was 2.2 μM. Use-dependent reduction of sodium currents at the hp of -100 mV was enhanced by orphenadrine at 0.1 μM, a clinically relevant concentration. This study suggests that blockade of sodium channels may contribute to clinical efficacy of orphenadrine (Supported by Telethon-Italy grant GGP04140).