Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against Na_v1.8 have shown that this channel contributes to experimental inflammatory and neuropathic pain. We report here the discovery of A-803467, a sodium channel blocker that potently blocks tetrodotoxin-resistant currents (IC₅₀ = 140 nM) and the generation of spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human Na_v1.8 (IC₅₀ = 8 nM) and was >100-fold selective vs. human Na_v1.2, Na_v1.3, Na_v1.5, and Na_v1.7 (IC₅₀ values ≥1 μM). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED₅₀ = 47 mg/kg, i.p.), sciatic nerve injury (ED₅₀ = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED₅₀ ≈ 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED₅₀ = 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of Na_v1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.