The goal of this proof-of-concept study was the fabrication of drug-loaded silk fibroin (SF) spheres under very mild processing conditions. The spheres were fabricated using the laminar jet break-up of an aqueous SF solution, which was induced by a nozzle vibrating at controlled frequency and amplitude. SF particles were spherical in shape as determined by SEM with diameters in the range of 101 microm to 440 microm, depending on the diameter of the nozzle and the treatment to induce water insolubility of SF. Both treatments, either methanol or exposure to water vapor, resulted in an increase in beta-sheet content as analyzed by FTIR. High encapsulation efficiencies, close to 100%, were obtained when salicylic acid and propranolol hydrochloride-loaded SF spheres were left untreated or exposed to water vapor. Methanol treatment resulted in drug leaching and lowered the overall encapsulation efficiency. When 9% SF solutions were used for SF sphere preparation, release rates were more sustained than from spheres made with 3% SF solutions, and propranolol hydrochloride release was more sustained than salicylic acid release. However, no difference in the release profiles was observed between methanol and water vapor treated SF spheres. Because of its very mild conditions, which are potentially advantageous for the encapsulation of sensitive drugs, we also tested this method for the encapsulation of insulin-like growth factor I (IGF-I). Again encapsulation efficiencies were close to 100%, even after treatment with methanol. IGF-I was continuously released over 7 weeks in bioactive form, as analyzed by the proliferation of MG-63 cells. These results favor further investigation of SF spheres as a platform for the controlled release of sensitive biologicals.