Acid Sensing Ion Channels (ASICs), are sodium channels gated by extracellular protons. ASIC1a is abundantly expressed in the peripheral and central nervous system. Proposed functions for ASIC1a include higher brain functions, such as learning and memory. Moreover, activation of ASIC1a contributes to neuronal death during brain ischemia. ASICs display current tachyphylaxis (repeated agonist applications lead to decreasing responses) in neurons. The mechanism of this tachyphylaxis is unknown. Here we found that, upon repeated pH 5 stimulation only ASIC1a currents show tachyphylaxis also in the Xenopus oocyte system, allowing us to study the mechanism of this tachyphylaxis. Higher proton concentrations enhanced tachyphylaxis, while higher extracellular calcium conc. slowed tachyphylaxis. Tachyphylaxis was use-dependent and needed opening of ASIC1a channels. Mutations that speed current desensitization abolished tachyphylaxis, indicating that the duration of channel opening was important. Moreover, intracellular acidification enhanced tachyphylaxis. We also found that ASIC1a is permeable to protons. Together, these results suggest that proton influx during ASIC1a opening negatively feed backs on channel activity, causing tachyphylaxis. Since ASIC1a activation contributes to neuronal death during brain ischemia, understanding tachyphylaxis of ASIC1a activity may help to reduce its pathological effect on neurons during ischemia.