Voltage-gated sodium channels can be characterized by their sensitivity to inhibitors. Na_v1.5 is sensitive to block by cadmium and extracellular QX-314, but relatively insensitive to tetrodotoxin and saxitoxin. Na_v1.4 is tetrodotoxin- and saxitoxin-sensitive but resistant to cadmium and extracellular QX-314. Na_v1.8 and Na_v1.9 generate slowly inactivating (I_TTXr-Slow) and persistent (I_TTXr-Per) currents in sensory neurons that are tetrodotoxin-resistant. Tetrodotoxin sensitivity is largely determined by the identity of a single residue; tyrosine 401 in Na_v1.4, cysteine 374 in Na_v1.5 and serine 356 and 355 in Na_v1.8 and Na_v1.9. We asked whether Na_v1.8 and Na_v1.9 share other pharmacological properties as a result of this serine residue. I_TTXr-Slow and I_TTXr-Per were saxitoxin-resistant and resistant to internal QX-314. I_TTXr-Slow was also resistant to external QX-314 and displayed a approximately fourfold higher sensitivity than I_TTXr-Per to cadmium. The impact of the serine residue was investigated by replacing tyrosine 401 in Na_v1.4 with serine (Y401S) or cysteine (Y401C). Both mutants were resistant to tetrodotoxin and saxitoxin. Whereas Na_v1.4-Y401C displayed an increased sensitivity to cadmium and extracellular QX-314, the serine substitution did not alter the sensitivity of Na_v1.4 to cadmium or QX-314. Our data indicates that while the serine residue determines the sensitivity of I_TTXr-Slow and I_TTXr-Per to tetrodotoxin and saxitoxin, it does not determine their insensitivity to QX-314 or their differential sensitivities to cadmium.