Acidosis is a common feature of neurological conditions including brain ischemia, epileptic seizures, and neurotrauma. Activation of Ca(2+)-permeable acid-sensing ion channels (ASIC1a) is involved in acidosis-mediated ischemic brain injury. Zn(2+) 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 Ca(2+) concentrations are inhibited dramatically by the physiological concentration of extracellular Zn(2+). In this report, we demonstrate that decreasing the concentration of the extracellular Zn(2+) significantly enhances acid-induced injury of HEK 293 cells, a cell line expressing homomeric ASIC1a-like channels, whereas increasing the concentration of extracellular Zn(2+) appears to be protective. Although increased concentrations of intracellular Zn(2+) have been shown to be detrimental to neurons, our findings may suggest that the physiological concentration of extracellular Zn(2+) might play a protective role in acidosis-induced, ASIC1a-mediated neuronal injury.