Zinc induces protein phosphatase 2A （PP2A） inactivation and tau hyperphosphorylation through PP2A （tyrosine 307） phosphorylation in cells and the brain, but whether Zn2＋ has a direct inhibitory effect on PP2A is not clear. Here we explored the effect of Zn2＋ on PP2A and their direct interaction in vitro. The results showed that Zn2＋ mimicked the inhibitory effect of okadaic acid on protein phosphatase and prevented tau dephosphorylation in N2a cell lysates. PP2A activity assays indicated that a low concentration （10 pmol/L） of Zn2＋ inhibited PP2A directly. Further Zn2＋-IDA-agarose affinity binding assays showed that Zn2＋ bound to and inhibited PP2Ac（51l-270） but not PP2Ac（1.50） or PP2Ac（27.309）. Taken together, Zn2＋ inhibits PP2A directly through binding to PP2Ac（51-270） in vitro.