We have developed a nanocomposite using a silica nanocomposite polyhedral oligomeric silsesquioxane (POSS) and poly(carbonate-urea)urethane (PCU) for potential use in cardiovascular bypass grafts and the microvascular component of artificial capillary beds. In this study, we sought to compare its antithrombogenicity to that of conventional polymers used in vascular bypass grafts so as to improve upon current patency rates, particularly in the microvascular setting. Using atomic force microscopy (AFM) and transmission electron microscopy (TEM), surface topography and composition were studied, respectively. The ability of the nanocomposite surface to repel both proteins and platelets in vitro was assessed using thromboelastography (TEG), fibrinogen ELISA assays, antifactor Xa assays, scanning electron microscopy (SEM), and platelet adsorption tests. TEG analysis showed a significant decrease in clot strength (one-way ANOVA, p < 0.001) and increase in clot lysis (one-way ANOVA, p < 0.0001) on the nanocomposite when compared to both poly(tetrafluoroethylene) (PTFE) and PCU. ELISA assays indicate lower adsorption of fibrinogen to the nanocomposite compared to PTFE (one-way ANOVA, p < 0.01). Interestingly, increasing the concentration of POSS nanocages within these polymers was shown to proportionately inhibit factor X activity. Platelet adsorption at 120 min was also lower compared to PTFE and PCU (two-way ANOVA, p < 0.05). SEM images showed a "speckled" morphologic pattern with Cooper grades I platelet adsorption morphology on the nanocomposite compared to PTFE with grade IV morphology. On the basis of these results, we concluded that POSS nanocomposites possess greater thromboresistance than PTFE and PCU, making it an ideal material for the construction of both bypass grafts and microvessels.