Hydrophilic-hydrophobic multiblock copolymers synthesized from telechelic oligomers of poly(ethylene oxide) (PEO) and polystyrene (PS) have been used to study the influence of hydrophilic and hydrophobic balance on interfacial interactions of these surfaces with blood components. In vitro coagulation assays show no inherent ability of these amphiphilic surfaces to affect contact activation or coagulation factors. In vitro platelet adhesion and release reactions from rabbit platelet-rich plasma were shown to be greatest on Biomer and PS homopolymer surfaces and least on cross-linked PEO surfaces, with the PEO-PS block copolymers demonstrating intermediate responses. These same substrates were tested in a new low-flow, low-shear arterio-artery shunt system in rabbits. Whole blood occlusion times were not a direct function of hydrophilic content as both PEO and PS homopolymers and Biomer showed short occlusion times, while PEO-PS block copolymers prolonged occlusion times considerably, depending on composition. Overall, results suggest that PEO-PS block copolymers promote unique whole blood responses in contrast to homopolymer and Biomer controls which are more complex than direct correlations to bulk hydrophilic and hydrophobic contents.