The changes of glycogen synthase kinase-3 (GSK-3) and protein phosphatase-2A (PP-2A), and the role of them in the regulation of the abnormally hyperphosphorylated some sites of tau in the cortex of diabetic rat were investigated. The diabetic rat model was induced by streptozotocin. The activities of GSK-3, PP-2A were measured by liquid scintillation for incorporated radioactivity in control, DM, DM + Li₂CO₃ groups. The level of hyperphosphorylated tau and the expression of ²PP-2A was measured respectively by Western blot. It is suggested that GSK-3 activity increases, PP-2A activity and expression decrease, and hyperphosphorylated tau be produced at Ser198/Ser199/Ser202 and Ser396/Ser404 in DM rats cortex. After the DM rat were treated with Li₂CO₃, the inhibition of GSK-3 activity and the improvement of PP-2A activity were found, and hyperphosphorylation of tau at Ser198/Ser199/Ser202 and Ser396/Ser404 were deduced. These studies firstly suggested that an increase of GSK-3 activity might inhibit PP-2A activity, and which produce hyperphosphorylated of tau at Ser198/Ser199/Ser202 and Ser396/Ser404 in DM rat cortex in common.