Polymers with mucoadhesive properties are universally used in the development of mucoadhesive drug delivery system. Their physicochemical properties as well as the mechanisms related to their adhesive actions draw great attention for the modification of mucoadhesive properties. In this study, relationships between physicochemical properties of hydroxypropyl methylcellulose (HPMC) compacts and mucoadhesive performance were investigated. Different commercial grades of HPMC (K3, E3, E5, E50, K4M, E4M and K15M) were prepared into compacts, and their surface hydrophilicity and hydration behavior were characterized. The in vitro mucoadhesive performance was determined by the tension strength between the compacts and different regions of mucous membrane (buccal, sublingual, stomach, and intestine). Positive correlations were found between: (1) viscosity of HPMC compacts and contact angle values measured by different simulated body fluids; (2) viscosity of HPMC compacts and in vitro mucoadhesive force; (3) contact angle values and in vitro mucoadhesive force. The hydration behavior exhibited improvement with the increasing viscosity of HPMC compacts. Moreover, the polar lipid content of each mucosa was likely an important factor affecting the mucoadhesion phenomenon. Different ratios of ethyl cellulose (EC) was mixed with HPMC grade K15M to form combination compacts for the purpose of modifying the surface property. The mucoadhesive mechanism of both different grades of HPMC compacts and combination compacts were studied via the thermodynamic analysis of Lifshiz-van der Waals interaction and Lewis acid-base interaction. The total free energy of adhesion (〖∆G〗^TOT) provided a prediction of an overall tendency of mucoadhesion, however, the results were showing disagreement with the measured mucoadhesive force. In general, the involving of EC in the combination compacts did not give a boost to the whole mucoadhesive performance.