Sulfonated poly(ethylene oxide) (PEO)-grafted polyurethane (PU) (PU-PEO-SO(3)) prepared by bulk modification was used to coat both PU heart valves and vascular grafts, and their in vivo biocompatibility was evaluated using a canine shunt method. The two devices were implanted for up to 39 days and retrieved at specific time points for the analysis of blood compatibility, biostability, and calcium deposition. When the surface of the retrieved specimens was examined using scanning electron microscopy, platelet adhesion and thrombus formation appeared to be significantly lesser formed on the PU-PEO-SO(3)-coated implants, compared with the untreated PUs. While molecular weights of untreated PUs were found by gel permeation chromatography to be decreased after 39 days from implantation, the same remained barely changed with the PU-PEO-SO(3)-coated ones. The inductively coupled plasma study indicated that the amount of deposited calcium was significantly reduced in the surface-modified PU implants. The efficacy of PU-PEO-SO(3)-coated implants in terms of blood compatibility, biostability, and calcification resistance may render them as a promising biomedical material in the application for blood/tissue-contacting tissues and organs.