Polymers are widely used for a large range of medical devices used as biomaterials on a temporary, intermittent, and long-term basis. It is now well accepted that the initial rapid adsorption of proteins to polymeric surfaces affects the performance of these biomaterials. However, protein adsorption to a polymer surface can be modulated by an appropriate design of the interface. Extensive study has shown that these interactions can be minimized by coating with a highly hydrated layer (hydrogel), by grafting on the surface different biomolecules, or by creating domains with chemical functions (charges, hydrophilic groups). Our laboratory has investigated the latter approach over the past 2 decades, in particular the synthesis and the biological activities of polymers to improve the biocompatibility of blood-contacting devices. These soluble and insoluble polymers were obtained by chemical substitution of macromolecular chains with suitable groups able to develop specific interactions with biological components. Applied to compatibility with the blood and the immune systems, this concept has been extended to interactions of polymeric biomaterials with eukaryotic and prokaryotic cells. The design of new biomaterials with low bacterial attachment is thus under intensive study. After a brief overview of current trends in the surface modifications of biocompatible materials, we will describe how biospecific polymers can be obtained and review our recent results on the inhibition of bacterial adhesion using one type of functionalized polymer obtained by random substitution. This strategy, applied to existing or new materials, seems promising for the limitation of biomaterial-associated infections.