Although the antinociceptive effects of N-palmitoyl-ethanolamine (PEA) were first characterized nearly 50 years ago, the identity of the mechanism that mediates these actions has not been elucidated. The present study investigated the contribution of K⁺ channels on peripheral antinociception induced by the CB₂ agonist PEA. Nociceptive thresholds to mechanical paw stimulation of Wistar rats treated with intraplantar prostaglandin E₂ to induce hyperalgesia were measured, and other agents were also given by local injection. PEA (5, 10, and 20 μg/paw) elicited a local peripheral antinociceptive effect. This effect was antagonized by glibenclamide, a selective blocker of ATP-sensitive K⁺ channels (20, 40, and 80 μg/paw). In addition, neither the voltage-dependent K⁺ channel–specific blocker tetraethylammonium (30 μg/paw) nor the small and large conductance blockers of Ca²⁺-activated K⁺ channels, dequalinium (50 μg/paw) and paxilline (20 μg/paw), respectively, were able to block the local antinociceptive effect of PEA. These results indicate that the activation of ATP-sensitive K⁺ channels could be the mechanism that induces peripheral antinociception by PEA and that voltage-dependent K⁺ channels and small and large conductance Ca²⁺-activated K⁺ channels do not appear to be involved in this mechanism.