Commercial polyurethanes, characterized by different soft/hard segment ratios, were used as matrices for the production of TPU/cellulose nanocrystal (CNC) nanocomposite films. TPU have excellent mechanical properties, chemical stability, easy processing, and can be used in some different application fields as biomedical sector. The selected grades exhibit excellent abrasion resistance, toughness, transparency, hydrolytic stability, and fungus resistance. In this context, the main objective was to understand how CNC interact with the different structures and composition of commercial TPU and to analyze its effect on the final mechanical, thermal, morphological, and water absorption properties of TPU/CNC systems. The results for morphological investigations underlined that CNC were well individualized and dispersed in TPU matrices. They were able to act as nucleation agents and as mechanical reinforcement phases in the thermoplastic matrices with an evident increase of Young's modulus and the tensile strength induced by the presence of CNC that offered a tailored reinforcement effect in both the elastic and plastic region. The interaction of all systems with water proved that all the materials saturated after 24 h and maintained their original shape, suggesting applicability also in high humidity environmental conditions of the proposed formulations. POLYM. ENG. SCI., 57:521-530, 2017. (c) 2017 Society of Plastics Engineers