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Poly(d , l -lactide- co -glycolide) (PLGA) microspheres have been used as an injectable depot for prolonged release of octreotide (Sandostatin LAR®), a peptide drug for the treatment of acromegaly and gastrointestinal tumors. However, acylation and incomplete release of the encapsulated octreotide, as well as acidic degradation product-induced inflammation are the major challenges hampering widespread clinical applications of this delivery system. The purpose of this study was to develop a novel octreotide-delivering system utilizing naturally derived biodegradable material, silk fibroin (SF). Octreotide acetate was encapsulated in the SF microspheres with a high loading (8–10 wt%) using polyethylene glycol (PEG)-assisted emulsification method. The octreotide-SF microspheres exhibited a silk I structure (low crystallinity) and burst release in in vitro release studies. Ethanol treatment after microsphere formation significantly increased β-sheet and silk II structure (high crystallinity) of the microspheres, significantly reducing the burst release and resulting in zero-order sustained release of octreotide over 102 days, and the data could be fit to the diffusion-driven release model. After the ethanol-treated microspheres were intramuscularly injected into rats at low (2 mg/kg) and high (8 mg/kg) octreotide doses, the plasma concentration of octreotide in the high dose group remained high (>50 pg/mL) at day 28 when compared to that of the control (pure drug at low dose) and low dose microsphere group. Interestingly, the plasma concentration for the high dose group at day 56 dramatically increased to >280 pg/mL observed at day 28. The low dose microsphere group showed a similar increase, but at a much lower level. The rebound octreotide level likely reflected degradation of the SF matrix which released tightly bound/trapped octreotide. Therefore, SF microspheres can deliver octreotide over a long period of time with release kinetics and the mechanism different from PLGA microsphere system. • Silk fibroin microspheres were fabricated using a novel PEG-assisted emulsification-condensation approach • A peptide drug, octreotide, was encapsulated in the microspheres at high loading and encapsulation efficiency • More than 100 days in vitro release under the sink condition was achieved successfully • Octreotide was released biphasically to blood for more than 56 days after a single-dose intramuscular injection in rats [ABSTRACT FROM AUTHOR]