Adenosine has been reported to provide cytoprotection in the central nervous systems as well as myocardium by activating cell surface adenosine receptors. However, the exact target and mechanism of its action still remain controversial. The present study was performed to examine whether adenosine has a protective effect against Aβ-induced injury in neuroglial cells. The astrocyte-derived human neuroglioma cell line, A172 cells, and Aβ25∼35 were employed to produce an experimental Aβ-induced glial cell injury model. Adenosine significantly prevented Aβ-induced apoptotic cell death. Studies using various nucleotide receptor agonists and antagonists suggested that the protection was mediated by A1 receptors. Adenosine attenuated Aβ-induced impairment in mitochondrial functional integrity as estimated by cellular ATP level and MTT reduction ability. In addition, adenosine prevented Aβ-induced mitochondrial permeability transition, release of cytochrome c into cytosol and subsequent activation of caspase-9. The protective effect of adenosine disappeared when cells were pretreated with 5-hydroxydecanoate, a selective blocker of the mitochondrial ATP-sensitive K⁢ channel. In conclusion, therefore we suggest that adenosine exerts protective effect against Aβ-induced cell death of A172 cells, and that the underlying mechanism of the protection may be attributed to preservation of mitochondrial functional integrity through opening of the mitochondrial ATP-sensitive K⁢ channels.