Objective To investigate the effect of silk fibroin (SF) on degradation and biocompatibility of poly (L-lactic acid-co-ε-caprolactone)(P[LLA-CL]) in vivo. Methods The scaffolds of P(LLA-CL) (w/w=1:1) blended with 25% of SF (SF/P[LLA-CL]) and P(LLA-CL) were prepared by electrospinning. Both kinds of scaffolds were subcutaneously implanted in 45 6-month-old rats for up to 6 months to evaluate their degradation and biocompatibility characteristics. Results Pathological sections showed P(LLA-CL) scaffold become swollen and began to separate into different layers after 3 months, and then become broken after 6 months; while SF/P(LLA-CL) scaffold largely maintained its structure after 6 months. Immunohistochemical staining showed a large number of macrophages on the surface and in P(LLA-CL) scaffolds 1 month after implantation, and they could still be found 3 months after implantation, accompanied by foreign body giant cells; while no obvious macrophages or foreign body giant cells were found in SF/P(LLA-CL) scaffolds at different time points. Examination of inflammatory gene expression showed that TNF-α and IL-10 expression in P(LLA-CL) scaffolds was significantly higher than that in SF/P(LLA-CL) scaffolds 1 week after implantation (P<0.05), the same was also true for TNF-α, IL-1β and IL-10 expression 1 month after implantation (P<0.05), for TNF-α and IL-10 expression 2 months after implantation (P<0.05), for TGF-β expression 3 months after implantation (P<0.05), and for IL-1β and TGF-β expression 6 months after implantation (P<0.05). Conclusion SF incorporation can delay degradation, reduce inflammation, and improve the biocompatibility of P(LLA-CL) scaffolds, which may provide reference for scaffold design in tissue engineering.