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In the present work, Microspheres of Entecavir using PLGA and Chitosan as polymers were formulated to deliver Entecavir via oral route. The results of this investigation indicate that Ionotropic gelation technique can be successfully employed to fabricate Entecavir microspheres. In this work an effort was made to formulate microsphere of Entecavir by using different polymers. Prepared formulations are evaluated for bulk density, tapped density, precent mucoadhesion, Percent compressibility, hausners ration, percentage yield, size and interaction study by FTIR and in vitro drug release. Formulation which passed all the evaluation parameters was considered as best formulation of Entecavir. The present study conclusively that Entecavir microsphere could be prepared successfully and formulation F3 was shows satisfactory result.