The outstanding hydrolytic and oxidative stabilities of polyisobutylene-based polyurethanes (PIB-based PUs) were reported earlier. Herein, we summarize recent investigations aimed at further enhancing hydrolytic-oxidative stabilities (in terms of resistance to aqueous buffer, nitric acid and CoCl2/H2O2) together with excellent mechanical properties. The purity and dryness of ingredients together with precise NCO/OH stoichiometry (similar to 1.05) are essential to obtain PIB-based PUs with improved properties. Static and dynamic mechanical properties were optimized by analyzing stress-strain traces, thermal (TGA, DSC) responses, self-organization (XRD) profiles, and rheological (DMA, creep) information. According to microstructure and surface analyses (AFM, contact angle) annealing increases the segregation of individual segments and increases surface hydrophobicity, which in turn enhances the shielding of hydrolytically oxidatively vulnerable carbamate bonds by inert PIB barriers, and thus significantly improves hydrolytic-oxidative stability. Annealing does not much affect bulk properties, such as static and dynamic mechanical and thermal properties; however, it increases damping over a wide temperature range. Annealed PIB-based PU containing 72.5% PIB exhibits outstanding hydrolytic-oxidative stability together with similar to 26 MPa tensile strength, similar to 500% elongation, and similar to 77 Microshore hardness. PIB-based PUs are significantly more resistant to hydrolytic and oxidative degradation than ElastEon (TM) E2A, a commercially available PDMS-based PU, widely used for medical applications. (C) 2015 Wiley Periodicals, Inc.