Acidosis is a common feature of neurological conditions including brain ischemia, epileptic seizures, and neurotrauma. Activation of Ca2+-permeable acid-sensing ion channels (ASIC1a) is involved in acidosis-mediated ischemic brain injury. Zn2+ is a divalent cation concentrated in nerve terminals in various brain regions, and is released into the extracellular space during excitatory stimulation. Our previous studies have demonstrated that the activities of ASIC1a containing channels and acid-induced increased intracellular Ca2+ concentrations are inhibited dramatically by the physiological concentration of extracellular Zn2+. In this report, we demonstrate that decreasing the concentration of the extracellular Zn2+ significantly enhances acid-induced injury of HEK 293 cells, a cell line expressing homomeric ASIC1a-like channels, whereas increasing the concentration of extracellular Zn2+ appears to be protective. Although increased concentrations of intracellular Zn2+ have been shown to be detrimental to neurons, our findings may suggest that the physiological concentration of extracellular Zn2+ might play a protective role in acidosis-induced, ASIC1a-mediated neuronal injury.