In this study, a novel electrospun hybrid scaffold was developed, which consists of a blend of a modified natural substance, hydroxypropyl starch (HPS) with a synthetic one, poly(ethylene oxide) (PEO). Nanofibers with varying polysaccharide contents were fabricated using water as solvent and the electrospinning process conditions investigated as a function of the weight ratio of the blend. The fibers were characterized through mean diameter and morphology by scanning electron microscopy. Micrographs clearly showed the effect of HPS/PEO weight ratio of the blend on the nanofibers formation. Stability of the fibers was enhanced by coating with hydrophobic poly(methyl methacrylate) (PMMA). In vitro degradation analysis of the coated mats after 1 month of immersion showed porous formation, whereas the fibrous structure was retained. The biological response of the mats against human fibroblasts proved that cells were able to adhere to and proliferate on the fibrous materials. Thus, the feasibility of producing nanofibers of HPS/PEO blends with high proportion of starch and their biocompatibility after coating with PMMA was demonstrated, indicating that these materials have potential to be used as scaffolds in tissue engineering applications. (c) 2012 Wiley Periodicals, Inc. J Appl Polym Sci. 127: 1475-1484, 2013