Of the various polymers used in medical devices, polyurethanes have been relatively successful because of their acceptable mechanical and biological properties. However, over the past decade, increasing concerns have arisen in relation to the long-term biostability of polyurethanes when exposed to the harsh environment of the human body. Lysosomal enzymes released from inflammatory cells have been proposed to be important mediators in the degradation of biomedical polyurethanes. In order to increase the biostability of polyurethanes to lysosomal enzymes, a series of surface-modifying macromolecules (SMMs) were synthesized in this work and then combined into a base polyurethane to reduce the material's susceptibility to hydrolysis. X-ray photoelectron spectroscopy (XPS) studies showed that the SMMs were enriched within the upper 10 nm of the surface. In vitro biodegradation test results indicated that the degradation of a polyester-urea-urethane could be inhibited by the new SMM surface. It was also found that different SMM formulations provided varying degrees of inhibition against the biodegradation of the polyester-urea-urethane. Certain formulations of the SMMs were shown to be physically incompatible with the polyurethane and distorted surface morphology to the extent that biodegradation was enhanced.