To improve the hemocompatibility of blood-compatiblematerials, antiplatelet drug dipyridamole (DIP) was encapsulated in polyurethane (PU) to form core-shell nanofibers by coaxial electrospinning method. PU solution and DIP/polycaprolactone compound solution served as shell and core fluid, respectively. Uniform fibers without beads, were fabricated and a clear core-shell structure was generated. The diameter of nanofibers and core structure increased with an increase in the flow rate of the core solution. X-Ray diffraction and differential scanning calorimeter showed that the whole system formed solid dispersion and DIP was dispersed in polymer matrix in an amorphous state. In vitro drug release test demonstrated that releasing curve had two phases consisting of initial burst release and sustained release governed by diffusion mechanism. A more flat curve occurred when the diameter of PU shell increased. In this case, the PU shell served as a barrier restricted DIP release from core drug reservoir. In vitro platelet adhesion test demonstrated that the DIP had maintained its antiplatelet effect after coaxial electrospinning process and could present distinguished antiplatelet activity after 7th and 30th days. Finally, DIP loaded core-shell nanofiber mats with good hemocompatibility, were conveniently fabricated by coaxial electrospinning, which has great potential in the field of tissue engineering vascular graft.