Hydrophobically substituted dextran (dextran phenoxy, DexP) and dextran phenoxy-poly( ethylene oxide) copolymers (DexP-PEO) have been used to modify the surface of polystyrene latex particles. To avoid polymer desorption in the presence of hydrophobic species such as proteins, the adsorbed layer was stabilized by chemical cross-linking and then characterized in terms of adsorbed amount, thickness, and stability. The interfacial concentration in anchoring phenoxy groups and the PEO grafting density were both varied, and their effects on nonspecific bovine serum albumin (BSA) adsorption were examined. It was found that the most important parameter in preventing BSA adsorption is the number of interactions between the adsorbed dextran and the surface, even in the presence of DexP-PEO layers with high grafting ratios of PEO chains. We also examined the ability of dextran layers to bind specifically concanavalin A (Con A) as the Con A molecule exhibits a good specific affinity for glucose-containing carbohydrates. Flocculation of DexP-modified particles by Con A was observed in the course of the experiments. All of these results are discussed in relation to the importance of polymer architecture and surface-protein interactions in protein rejection by dextran and dextran-PEO coatings.