AIM: To study the effect of caffeine on apoptosis induced by inhibition of I-phosphaddylinositol 3-kinase in cerebellur granule neurons. METHODS: Cerebellar granule neurons culture, agar gel eletrophoresis, and tess-activated protein kinase (SAPK)/c-Jun N-tennial, protein kimtse (JNK) assay kit to mesure SAPK/JNK activity. RESULTS: LY294002 evoked apoptosis concentmtion-dependemly in cerebellar granule neurons. But death resulting from LY2940002 was prevented by caffeine in a concentratlon-dependent manner. The survival effect of caffeine was not affected by inbitors of ryanodine-sensitive Ca2+ release, nor was it inhibited by L-type channel blockers and N-methyi-D-aspartate (NMDA) receptor blocker. In addition, RP-cAMP, H89, and KN62 were not able to inhibit the protective effect of caffeine. Phosphorylation of c-Jun was necessary for the induction of apoptosis induced by LY294002 in cerebellar granule neurons. But caffeine lirectly inhibited the activation of JNK and decreased phospho-c-Jun in granule neurons. CONCLUSION: Caffeine inhibited the activation of JNK and decremsed the phosphorylabon of c-Jun to protect granule neurons from LY294002-ieduced apoptosis.