Core-shell nanofiber of silk fibroin as shell and blend of salicylic acid/poly(vinyl alcohol) as core was fabricated successfully via coaxial electrospinning. Effects of concentration, viscosity, and electrical conductivity of the core and shell solutions on the final diameter of nanofibers and release behavior of salicylic acid were studied by viscometry, electrical conductometry, ultraviolet spectrophotometry, scanning electron microscope and transmission electron microscope methods. Response surface methodology was used to predict the relation between average fiber diameter as well as release rate of salicylic acid with core and shell concentrations. Direct relation between final nanofibers diameters and shell solution concentration was observed, while increase in core solution concentration was not significantly affected the final diameter of electrospun nanofibers. According to the results of release profiles, ratio of component in core and shell are effective parameters in rate and profile of salicylic acid release from these structures. Response surface methodology analysis indicates that the nanofibers diameters are more responsive to the changes in shell solution concentration and the release rate of salicylic acid is responsive to the changes in both shell and core solutions concentrations.