The properties of macromolecules in presence of an interface could be considerably modified due to confinement effects. When phase separations are performed in nanoconfined domains, the concurrent presence of high-energy interfaces and conformational entropy constraints of the macromolecules causes profound differences in polymer aggregation behavior. Here, thermodynamics of a polymer chain in solution, confined by a three-dimensional cubic interface, is studied by means of Monte Carlo method, focusing on the chain conformational entropy penalty arising from the excluded volume effects. The presented method might become a general tool for a preliminary evaluation of the thermodynamic effects due to the confinement of a polymer system. Further, the interface effects on Thermally Induced Phase Separation (TIPS) of polymer solutions, confined by High-Pressure Homogenization, are experimentally studied, regarding final morphologies. It is confirmed how peculiar polymer morphologies are obtained only when the TIPS develops under nanoconfinement degrees above a threshold one. (c) 2017 American Institute of Chemical Engineers AIChE J, 64: 416-426, 2018