Abstract: High purity Form II crystals of clarithromycin can be easily prepared in a high yield by a process comprising the steps of: protecting the 9-oxime hydroxy group of erythromycin A 9-oxime or a salt thereof with a tropyl group and the 2′- and 4″-hydroxy groups with trimethylsilyl groups; reacting 2′,4″-O-bis(trimethylsilyl)erythromycin A 9-O-tropyloxime with a methylating agent; removing the protecting groups and the oxime group of 2′,4″-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-O-tropyloxime to obtain crude clarithromycin; treating the crude clarithromycin with methanesulfonic acid in a mixture of a water-miscible organic solvent and water to obtain crystalline clarithromycin mesylate trihydrate; and neutralizing the crystalline clarithromycin mesylate trihydrate with aqueous ammonia in a mixture of a water-miscible organic solvent and water.