In this work, a new microsphere delivery system comprising calcium alginate microcores surrounded by a biodegradable poly-DL-lactide-poly(ethylene glycol) (PELA) coat was designed to improve the loading efficiency and stability of peptide drugs. Recombinant interferon (IFN)-alpha-2a, used as a model peptide drug, was efficiently entrapped within the alginate microcores using a high-speed stirrer and then microencapsulated into PELA copolymer using a water-in-oil-in-water solvent extraction method. Microspheres were characterized in terms of morphology, size and distribution, encapsulation efficiency, IFN biological activity retention and in-vitro peptide release. The IFN potency test showed that IFN entrapped in the core-coated microspheres could retain its biological activity during the encapsulation and release procedure. The release profiles were determined by the measurement of peptide presenting in the release medium at various intervals. The IFN potency, calculated by the Wish cells/vesicular stomatitis virus system, was used to determine IFN biological activity. The results showed that the core-coated microspheres could stabilize IFN in the PELA matrix. We compared the new deliverysystem with conventional microsphere delivery systems based on biodegradable poly-DL-lactide and poly-DL-lactide-poly(ethylene glycol). The core-coated microspheres had the highest amount of entrapment, encapsulation efficiency and biological activity retention. The extent of burst release (14%) from the core-coated microspheres in the initial protein release was much lower than the 31% burst release from the conventional microspheres. In conclusion, this work presents a new approach for water-soluble macromolecular drugs delivery (e.g. protein, peptide drugs, vaccines).