To investigate the effect of the hydrophilic and hydrophobic microdomain structure on blood compatibility, a series of interpenetrating polymer networks (IPNs) composed of hydrophilic polyurethane (PU) and hydrophobic polystyrene (PS) was prepared. One series was prepared with varying cross-link densities of each network, the other with varying hydrophilicity of the PU component. All PU/PS IPNs exhibited microphase-separated structures that had dispersed PS domains in the continuous PU matrix. The domain size decreased with decreasing the hydrophilicity of the PU component and increasing the cross-link density of each network. As the cross-link density and hydrophobicity of the PU component was increased, an inward shift of Tps was observed, which was due to the decrease in phase separation between the hydrophobic PS component and hydrophilic PU component. In the in vitro platelet adhesion test, as the microdomain size of PU/PS IPN surface decreased, the number of adhered platelets on the PU/PS IPN surface was reduced and deformation of the adhered platelets decreased. It could be concluded that blood compatibility of PU/PS IPN was mainly affected by the degree of mixing between PU and PS component, which was reflected by the domain size of PS rich phase.