Six flexible-leaflet prosthetic heart valves, fabricated from a polyetherurethaneurea (PEUE), underwent long-term fatigue and calcification testing. Three valves exceeded 800 million cycles without failure. Three valves failed at 775, 460, and 544 million cycles, respectively. Calcification was observed with and without associated failure in regions of high strain. Comparison with similar valves fabricated from a polyetherurethane (PEU) suggests that the PEU is likely to fail sooner as a valve leaflet. Localized calcification developed in PEUE leaflets at the primary failure site of PEU leaflets, close to the coaptation region of the three leaflets. The failure mode in PEU valves had the appearance of abrasion wear associated with calcification. High strains in the same area may render the PEUE leaflets vulnerable to calcification. Intrinsic calcification of this type, however, is a long-term phenomenon unlikely to cause early valve failure. Both polymers performed similarly during static in vitro and in vivo calcification testing and demonstrated a much lesser degree of calcification than bioprosthetic types of valve materials. Polyurethane valves can achieve the durabilities required of an implantable prosthetic valve, equaling the fatigue life of currently available bioprosthetic valves.