Temperature- and pH-sensitive interpenetrating polymer networks (IPNs) and semi-interpenetrating polymer networks (s-IPNs) were γ-ray grafted onto polyurethane (Tecoflex®; TFX) to obtain vancomycin-eluting implantable medical devices with minimized risk of infections. N-isopropylacrylamide (NIPAAm) was grafted onto TFX catheters and films via a preirradiation oxidative method (method P) or via a direct method (method D). The PNIPAAm network facilitated acrylic acid (AAc) inclusion and subsequent polymerization/crosslinking, under specific reaction conditions. IPNs and s-IPNs systems were characterized regarding the amount of grafted polymers, surface properties (FTIR-ATR, ESEM, EDX), thermal behavior (DSC), and their temperature- and pH-responsiveness. Loading and release of vancomycin for preventing in vitro growth of Staphylococcus aureus were also evaluated. Antimicrobial activity tests and hemo- (hemolysis, protein adsorption, thrombogenicity) and cyto-compatibility (cell viability and production of cytokines and NO) assays indicated that the modification of TFX by γ-radiation may improve the performance of polyurethanes for biomedical applications. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2014, 131, 39992.