Thermoplastic polycarbonate urethanes (PCUs), have promise in many biomedical applications due to their low stiffness, favorable biocompatibility, and high strength. The long-term performance of PCU implants in load-bearing applications remains to be seen, and will depend in part on the material fatigue properties. Optimizing implants for success in fatigue-prone applications depends on a strong understanding of the relationship between material structure and fatigue performance, a surprisingly understudied area. In this study, we sought to develop relationships between PCU structure and mechanical properties, including fatigue, for three soft PCUs with systematically varied ratios of hard and soft segments. In addition, we compared injection molded controls to 3D printed (fused deposition modeling, FDM) varieties to examine the effects of such processing. Results indicate that increased hard segment content leads to increased stiffness, increased shear failure stress, and improvements in tensile fatigue from a stress-based standpoint despite relatively uniform tensile strength for the tested grades. Effects of hard segment content on tensile failure strain, and strain-based fatigue performance, were more complex and largely influenced by microphase organization and interaction. FDM samples matched or exceeded injection molded controls in terms of tensile failure stress and strain, compressive properties, shear strength, and tensile fatigue. The success of FDM samples is attributed in part to favorable printing parameters and the toughness of PCU which results in lower flaw sensitivity. (C) 2016 Elsevier Ltd. All rights reserved.