The extent of the hydrolytic degradation of aliphatic polyurethane (PU) films made from polycarbonate-based aliphatic macrodiol (MD), diisocyanate-1,6-hexane, butane-1,4-diol (BD) and D,L-lactide-based oligomeric diol (DLL) was tested in phosphate-buffered saline (PBS) for a period of up to 12 months. Two macrodiols of equal molecular weight (∼2000 Da), differing in chain composition and regularity, and equal MD-to-BD-to-DLL molar ratios were chosen for the PU synthesis. The isocyanate-to-total hydroxyl group ratio was kept constant at 1.05. The functional properties of raw four-component polyurethane films and samples immersed for 1, 3, 6, 9 and 12 months in a model physiological environment (37 °C, pH = 7.4) were studied from the segmental up to the macroscopic level. Tensile testing and water uptake experiments, as well as DSC, SEM, AFM, FTIR and WAXD analyses, were used for the comprehensive characterization of the raw and PBS-treated films. The study shows that the untreated four-component PU films are highly elastomeric materials with very high tensile strength and suitable thermal properties for potential medical coating/film applications. The DLL oligomeric diol turned out to be a very efficiently degradable unit, leading to substantial mechanical property deterioration. The products of more regular macrodiol have higher tendency to the degradation process; 89 % or 94 % of the original toughness value is lost in just 12 months of immersion. The studied type of PU can be practically used either as fairly stable high-performance elastomers for short-term applications (up to 3 months) or as degradable materials, when the time of exposure to the physiology-mimicking conditions is sufficient.