The objective of this study was to identify and evaluate key polymer properties affecting direct compression and drug release from water-insoluble matrices. Commonly used polymers, such as Kollidon® SR, Eudragit® RS and ethyl cellulose, were characterized, formulated into tablets and compared with regard to their properties in dry and wet state. A similar site percolation threshold of 65% v/v was found for all polymers in dry state. Key parameters influencing polymer compactibility were the surface properties and the glass transition temperature (Tg), affecting polymer elasticity and particle size-dependent binding. The important properties observed in dry state also governed matrix characteristics and therefore drug release in wet state. A low Tg (Kollidon® SR < Eudragit® RS) decreased the percolation threshold, particle size effect and tortuosity, but increased permeability and sensitivity to heat/humidity treatment. Hence, lower permeability and higher stability are benefits of a high-Tg polymer (ethyl cellulose). However, release retardation was observed in the same order as matrix integrity (Eudragit® RS < ethyl cellulose < Kollidon® SR), as the high permeability was counteracted by PVP in case of Kollidon® SR. Therefore, the Tg and composition of a polymer need to be considered in polymer design and formulation of controlled-release matrix systems.