In this study, monolithic and core/shell polyurethane (PU) nanofibers were fabricated by single and coaxial electrospinning techniques, respectively. An antivirus drug, Acyclovir (ACY), was loaded on PU nanofibers. The physical condition and interaction of the loaded ACY within these nanofibers were studied by FTIR, XRD, DSC, SEM, and TEM. In vitro tests exhibited an obvious difference in the release pattern between monolithic and core/shell nanofibers and burst release in monolithic nanofibers could be controlled by core/shell structure. Release profile was found to follow Korsmeyere-Peppas model with Fickian diffusion mechanism. Our study demonstrated that the ACY-loaded core/shell nanofibers might serve as a device for drug delivery systems. (C) 2016 Wiley Periodicals, Inc.