Novel polyurethane (PU) scaffold materials were designed and prepared on the basis of a coupling reaction between tetra-hydroxyl-terminated poly(butadiene-co-acrylonitrile) prepolymer (THTPBA) and poly(ethylene glycol) (PEG) via 1,6-hexamethylene diisocyanate as anchor molecule. The hydrophilicity, degradability, mechanical, and biomedical properties of the THTPBA/PEG PU materials were scrutinized by swelling and goniometry, FTIR and gravimetry methods, tensile stress-strain measurements and hemolysis, platelet activation, dynamic (erythrocyte aggregation) and static coagulation as well as MTT assays. The experimental results indicated that the hydrophilicity and mass loss were enhanced with increased concentrations and molecular weight (MW) of PEG. The degradation may be attributable to the cleavage of urethane or ester bonds in polymer chains. The in vitro blood compatibility and MTT cytotoxicity investigations elicited that the MW of PEG and mass ratios of THTPBA to PEG had important influence on the biomedical properties. The tensile stress-strain investigations showed that the highly crosslinked architecture offered high elastic modulus and mechanical strength. The PU scaffolds with proper component ratios and MW of PEG exhibited improved mechanical properties and biocompatibility as well as low toxicity, and can be employed as potential candidates for blood-contacting applications.