Abstract: AIM　To study the effect of the specific p38 MAPK inhibitor SB203580 on apoptosis induced by PI-3-K inhibitor LY294002 and its mechanisms in cerebellar granule neurons.METHODS　Cerebellar granule neurons culture, agar gel eletrophoresis, and SAPK/JNK assay kit were used to measure SAPK/JNK activity. RESULTS　Cultured cerebellar granule neurons died by apoptosis in a concentration-dependent manner when treated with LY294002, a specific inhibitor of PI-3-K. But the specific p38 MAPK inhibitor SB203580 promoted the survival of cerebellar granule neurons by blocking apoptosis. This protective action was shown to be in a concentration-dependent manner. The expression and phosphorylation of c-Jun increased, and the activity of c-Jun N-terminal protein kinase (JNK) was elevated when cerebellar granule neurons were cultured with LY294002 50 μmmol.L^-1 in cHK medium. But when the cerebellar granule neurons treated with LY294002 50 μmmol.L_-1 were exposed to SB203580 25 μmmol.L^-1, the expression and phosphorylation of c-Jun， and the activity of JNK all decreased evidently. CONCLUSION　SB203580 inhibited the activation of JNK and decreased the expression and phosphorylation of c-Jun to protect granule neurons from apoptosis induced by LY294002.