In the skin of humans and rodents, local pressure induces localized cutaneous vasodilation, which may be protective against pressure-induced microvascular dysfunction and lesion formation. Once activated by the local pressure application, the capsaicin-sensitive nerve fibers release neuropeptides that act on the endothelium to synthesize and release NO and prostaglandins, leading to the development of the cutaneous pressure-induced vasodilation (PIV). The present study was undertaken to test in vivo the hypothesis that PIV is mediated or modulated by differential activation of potassium (K⁺) channels in anesthetized rats using pharmacological methods. Local pressure was applied at 11.1 Pa s^-1. Endothelium-independent and dependent vasodilation was tested using iontophoretic delivery of sodium nitroprusside (SNP) and acetylcholine (ACh), respectively, and was correlated with PIV response. PIV was reduced following systemic administration of tetraethylammonium (TEA, a non-specific K⁺ channels blocker), iberiotoxin (a specific high conductance Ca²⁺-activated K⁺ (BK_Ca) channels blocker) and glibenclamide (a specific ATP-sensitive K⁺ (K_ATP) channels blocker), whereas PIV was unchanged by apamin (a specific low conductance Ca²⁺-activated K⁺ (SK_Ca) channels blocker) and 4-aminopyridine (4-AP, a specific voltage-sensitive K⁺ (K_v) channels blocker). The responses to SNP and ACh were reduced by iberiotoxin, but were unchanged by glibenclamide. We conclude that the cellular mechanism of PIV in skin involves BK_Ca and K_ATP channels. We suggest that the opening of BK_Ca and K_ATP channels contribute to the hyperpolarization of vascular smooth muscle cells to produce PIV development mainly via the NO and PG pathways, respectively.