The core-shell structure nanofibers of poly(ethylene oxide)/chitosan have been electrospun from the homogeneous solution of chitosan (CS, as shell) and poly(ethylene oxide) (PEO, as core). The preparation process of core-shell structure was quite simple and efficient without any complex electrospinning setup or post-treatment. The core-shell structure and major component of each layer had been characterized by TEM and further supported by SEM, XRD, DSC, and EDS studies. The blending ratio of PEO and CS, molecular weight of chitosan, and temperature of electrospinning were thought to be the key influence factors on the formation of core-shell structure. Because of the chitosan outer layer and shell thickness being controllable, the core-shell structure nanofiber would show a potential application for the biomedical fields involving wound care and tissue engineering.