Open cage polyhedral oligomeric silsesquioxane (POSS) was firstly used to modify polyurethane (PU) to prepare a POSS-PU composite. Then a POSS-PU nanofiber membrane was prepared by electrospinning technology. The hydrophilic/hydrophobic properties, fiber morphology and biocompatibility of the POSS-PU nanofibers membrane were investigated. Contact angle increased by 24.3 degrees for 2 wt% POSS-PU nanofibers membrane compared to PU. The ability of the nanofibers membrane surface to repel proteins and platelets was assessed by using platelet adhesion test and BSA static protein-adsorption experiment. Platelet adsorption amount obviously decreased compared with PU and very few platelet was adhered on the surfaces of nanofibers membranes when 1 wt% POSS was added. Protein adsorption was also decreased with addition of POSS. Hemolysis tests showed that hemolysis rate localized in the desired range of values (<5%) for all nanofibers membrane. Moreover, the antibacterial activity of nanofibers membranes was obviously improved after addition of POSS.