Passive muscle stretch performed during a period of post-exercise muscle ischemia (PEMI) increases muscle sympathetic nerve activity (MSNA), and this suggests that the muscle metabolites may sensitize mechanoreceptors in healthy humans. However, the responsible substance(s) has not been studied thoroughly in humans. Human and animal studies suggest that cyclooxygenase products sensitize muscle mechanoreceptors. Thus, we hypothesized that local cyclooxygenase inhibition in exercising muscles could attenuate MSNA responses to passive muscle stretch during PEMI. Blood pressure (Finapres), heart rate, and MSNA (microneurography) responses to passive muscle stretch were assessed in 13 young healthy subjects during PEMI before and after cyclooxygenase inhibition, which was accomplished by local infusion of 6 mg ketorolac tromethamine in saline via Bier block. In the second experiment, the same amount of saline was infused via the Bier block. Ketorolac Bier block decreased prostaglandin synthesis to ~34% of the baseline. Before ketorolac Bier block, passive muscle stretch evoked significant increases in MSNA (<I>P</I> < 0.005) and mean arterial blood pressure (<I>P</I> < 0.02). After ketorolac Bier block, passive muscle stretch did not evoke significant responses in MSNA (<I>P</I> = 0.11) or mean arterial blood pressure (<I>P</I> = 0.83). Saline Bier block had no effect on the MSNA or blood pressure response to ischemic stretch. These observations indicate that cyclooxygenase inhibition attenuates MSNA responses seen during PEMI, and suggest that cyclooxygenase products sensitize the muscle mechanoreceptors.