Acid sensing ion channel subtype 3 (ASIC3) is responsive to acid in the extracellular medium. Prior studies suggest that muscle metabolite lactic acid and ASIC play a role in muscle afferent mediated reflex sympathetic response. Also, femoral occlusion increases the reflex sympathetic nerve response. Thus, we tested the hypothesis that enhanced ASIC3 expression and its responsiveness in primary afferent neurons innervating muscles contribute to the exaggerated reflex sympathetic responses after femoral occlusion. The femoral occlusion was induced by the femoral artery ligation in rats. First, we employed Western blot to examine expression of ASIC3 in dorsal root ganglion (DRG). The data showed that 24 hrs of femoral occlusion led to upregulation of ASIC3 expression in DRG (optical density: 0.93 ± 0.08 in control vs. 1.47 ± 0.04 after occlusion, P<0.05), e.g. 1.58‐fold increase. Second, experiments using whole cell patch‐clamp demonstrated that current amplitude of DRG neurons innervating muscle was larger in response to a lower pH in femoral occlusion. Third, responses of renal sympathetic nerve activity and blood pressure to acid injected into the arterial blood supply of hindlimb muscles were also enhanced after the ligation. This study suggests that ASIC3 has an important contribution to augmented sympathetic responsiveness after femoral occlusion. (Supported by R01 HL078866 and R01 HL090720).