The nanofibers produced from the regenerated Bombyx mori silk are the ideal candidate for tissue engineering scaffolds because of the advantage of having high surface area to volume ratio. We carried out the comparison of mechanical and biological properties between natural and synthetic polymeric nanofibers fabricated by co-electrospinning procedure. Various blends of regenerated silk with 1% (w/w) Type I collagen and 1% (w/w) polylactic-co-glycolic acid (PLAGA) were obtained using Hexafluoro isopropanol (HFIP) as a solvent. The parameters for electrospinning were optimized for fabricating the scaffolds with relatively uniform fiber diameters (approximately 400 nm). The morphology of electrospun fibers was characterized by environmental scanning electron microscopy (ESEM). The mechanical properties were determined via microtensile testing and cell-scaffolds interaction study was conducted using primary fetal bovine osteoblasts cells. Our results suggested that elasticity of silk nanofibers was altered with the incorporation of collagen and PLAGA. The elongation of silk nanofibers changed from 5.54 +/- 0.25% to 6.26 +/- 0.63% for silk-collagen nanofibers and to 9.86 +/- 0.22% for silk-PLAGA nanofibers. Silk nanofibers had comparable biocompatibility to collagen nanofibers. This proves that silk can be used instead of collagen in fabricating tissue engineering scaffolds. Consequently Silk can be employed as a cheaper alternative for collagen to fabricate tissue engineering scaffold, with adequate mechanical properties, and with equal capability of growing and differentiating osteoblast cells.