Ion implantation is a simple single-step process that is flexible and versatile for the modification of the properties of a material. Although widely applied to bulk materials, its use in polymeric materials with nanoscaled geometries is virtually unknown. We chose to investigate the use of ion beam modification of electrospun poly(vinyl alcohol) (PVA) nanofibers and study their cell compatibility properties. PVA is a FDA approved, widely used biocompatible polymer. Due to its high hydrophilicity, PVA does not favor cell attachment and is seldom considered as a scaffold material for use in regenerative medicine. Past efforts to improve cell compatibility included surface functionalization with cell-adhesive proteins or peptides and coating or blending with bioactive macromolecules. We developed a broad-energy-range ion implantation process to modify electrospun PVA nanofibrous scaffold. N⁺ and He⁺ ion implantations were used to create amide and carboxyl functional groups, respectively, in the scaffolds. The fibrillar structure of the scaffold was preserved during the ion implantation process to maintain the structural integrity and similarity to that of the native extracellular matrix in tissue. Cell compatibility was assessed in vitro using primary human skin fibroblasts. Successful cell adhesion, proliferation and normal cell morphology on the ion implanted scaffolds were confirmed by microscopy, while cells failed to adhere on the unmodified PVA surface. Cell proliferation was found to be a function of ion dose and the specific chemical functionalities introduced. Ion implantation of biocompatible nanofibers thus provides an attractive approach to create cell compatible substrates for tissue regeneration applications.