The chemical reactivity of epoxide molecules toward silk fibroin was investigated by determining the rate of conversion of reactive amino acid residues. Significant differences were found between two different bifunctional epoxides, diglycidyl ethers of ethylene glycol (E) and resorcinol (R), the former reacting at a higher extent with arginine and tyrosine. The moisture regain decreased by reaction with epoxides, at a variable rate and extent, according to the hydrophobic / hydrophilic properties of epoxides. A two-step behavior was observed when moisture regain values relating to the silk content in modified silk fibers were plotted as a function of the weight gain. Dynamic mechanical data showed that the major loss peak became broader and its temperature shifted to lower values following the increase of weight gain. The loss peak temperatures showed a linear relationship with the amount of weight gain. The fine structural changes induced by reaction with epoxides will be discussed in terms of chemical and steric factors of the epoxides, as well as of epoxide location within the different structural domains of silk fibers.