The oxidative/hydrolytic stability of polyurethanes (PUs) containing exclusively polyisobutylene (PIB), or mixed PIB/polytetramethylene oxide (PTMO), or mixed PIB/polyhexamethylene carbonate (PC) soft segments was investigated. The tensile strengths and elongations of various PUs were determined before and after agitating in 35% HNO3 or 20% H2O2/0.1 M CoCl2 solutions and retentions were quantified. The presence of PIB imparts significant oxidative/hydrolytic resistance. The tensile strength and elongation of PUs containing 70% PIB, or those of mixed PIB/PC soft segments with 50% PIB, remained essentially unchanged upon exposure to HNO3; in contrast, PUs containing mixed PIB/PTMO soft segments with 50% PIB underwent significant degradation. The tensile strength of PUs with mixed PIB/PC (60/10%) soft segment increased after exposure to HNO3, most likely because of oxidative crosslinking of PC segments. PIB/PTMO- and PIB/PC-based PUs and commercially available PUs (Elast-Eon (R) e and Carbothane (R)) were exposed to H2O2/CoCl2 solutions for up to 14 weeks. Although the experimental PIB/PC-based PUs exhibited negligible change in mechanical properties and no surface damage, ElastEon (R) and Carbothane (R) showed significant surface damage. PIB-based polyureas and Bionate (R) were implanted in rats for 4 weeks in vivo, and their biocompatibility was investigated. The biocompatibility of PIB-based materials was superior to Bionate (R). (C) 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2194-2203, 2010