Tumor necrosis factor-α (TNFα) is a proinflammatory cytokine involved in the development and maintenance of inflammatory and neuropathic pain conditions. TNFα can have long-lasting effects by regulating the expression of a variety of inflammatory mediators, including other cytokines and TNFα itself. However, the speed with which TNFα induces tactile and thermal hypersensitivity suggests that transcriptional regulation cannot fully account for its sensitizing effects, and some recent findings suggest that TNFα may act directly on primary afferent neurons to induce pain hypersensitivity. In the present study, we show that peripheral administration of TNFα induces thermal hypersensitivity in wild-type mice but not in transient receptor potential vanilloid receptor TRPV1 –/– mice. In contrast, TNFα produced equivalent mechanical hypersensitivity in TRPV1 –/– mice and wild-type littermates, suggesting a role for TRPV1 in TNFα-induced thermal, but not mechanical, hypersensitivity. Because tetrodotoxin (TTX)-resistant Na + channels are a critical site of modulation underlying mechanical hypersensitivity in inflammatory and neuropathic pain conditions, we tested the effects of TNFα on these channels in isolated mouse dorsal root ganglion (DRG) neurons. We report that acute application of TNFα rapidly enhances TTX-resistant Na + currents in isolated DRG neurons. This potentiation of TTX-resistant currents by TNFα is dramatically reduced in DRG neurons from TNF receptor 1 (TNFR1) knock-out mice and is blocked by the p38 mitogen-activated protein kinase inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole]. Mechanical hypersensitivity induced by peripherally applied TNFα is also significantly reduced by SB202190. These results suggest that TNFα may induce acute peripheral mechanical sensitization by acting directly on TNFR1 in primary afferent neurons, resulting in p38-dependent modulation of TTX-resistant Na + channels.