The swelling behavior of hydroxypropyl methyl cellulose (HMPC) in organic-aqueous mixtures is investigated via solution calorimetry. The polymer is stirred in a mixture of acetone:isopropyl acetate, water is injected into the system, and the heat released due to the polymer swelling is recorded by the calorimeter. A systematic study of the heat outputs at various acetone:isopropyl acetate:water compositions indicates that the swelling of the polymer is highly influenced by the solution composition. The increased swelling noted in isopropyl acetate rich compositions is attributed to the enhanced availability of water to interact with the polymer; the converse is true for the acetone rich systems. Calculations of the water activity in these different solvent systems substantiate this understanding, as the water activity is greater in isopropyl acetate rich compositions. Increased swelling was also noted at elevated temperatures. The understanding of HPMC behavior elucidated here allows for control over the polymer swelling in binary organic-water systems, and can be used to design non-aqueous granulation processes incorporating HPMC.