Abstract: Polyurethane prepolymer (PUP) was synthesized by using polyethylene glycol (PEG) and polypropylene glycol (PPG) as the soft segments,isophorone diisocyanate (IPDI) as the hard segment,dimethylol propionic acid (DMPA) and diethylene glycol (DEG) as chain extenders,triethylamine (TEA) as neutralizer.A series of silk fibroin-polyurethane composite hydrogels were synthesized through an orthogonal experiment with four factors and four levels.The four afctors were the molecular weight of PEG together with -NCO/-OH (n/n),PEG/(PEG+PPG) (n/n),SF/(SF+PU) (m/m).The compression resistance properties of hydrogels were tested by unconfined compression test and the results were analyzed by variance analysis.The results showed that the molecular weight of PEG had the most significant effect on the compression resistance properties of hydrogels.The compression modulus of silk fibroin-polyurethane composite hydrogels was between 0.35—1.20 MPa when the molecular weight of PEG was 600,1 000,2 000 and 4 000 respectively.