This study aimed to fabricate nanofibrous scaffolds which could biomimic the natural extracellular matrix from aqueous solutions of silk fibroin and hyaluronic acid blends (SF/HA) by means of electrospinning. Scanning electronic microscopy results indicated that electrospun SF/HA nanofibers were ribbon-shaped and their average width obviously decreased with the increase of HA content. However, there is no fiber observed when the volume of HA further increased to 50% of overall volume. After being treated with 75% ethanol vapor for 24 h, the fibers still remained their fibrous morphologies and presented good capability of water-resistance. Fourier transform infrared attenuated total reflectance spectroscopy, C-13-CP-MAS nuclear magnetic resonance and differential scanning calorimetry results revealed that HA did not induce SF conformation from random coil to beta-sheet. SF conformation converted from random coil to beta-sheet after being treated with 75% ethanol vapor. Cell viability studies demonstrated that SF/HA nanofibrous scaffolds significantly promoted cell proliferation. Electrospun SF/HA nanofibers may provide an ideal biomimic tissue-engineering scaffold or vehicle for water-soluble drugs. (C) Koninklijke Brill NV, Leiden, 2011