Abstract: Clarithromycin (CLA) belongs to the second generation macrolide antibiotic. The commercial crystal form of CLA is form II, and it exhibits the poor compressibility during the tablet pressing process. Since the crystal form of drugs has a significant effect on their mechanical properties, from the perspective of crystallography, this study investigated the difference of the compressibility between CLA form I and form II, and analyzed the mechanism that led to such difference. On the other hand, from the perspective of pharmaceutics, we also studied the effect of filler on the compressibility of form II. It was found that CLA form I had improved plastic deformation than form II because of the slip planes in its crystal structure leading to the better compressibility. Moreover, microcrystalline cellulose, pre-gelatinized starch and lactose monohydrate could improve the compressibility of form II, and microcrystalline cellulose showed the best effect. We improve the compressibility of CLA from crystal form and filler, and also lay a foundation for the development of CLA solid preparations.