Using recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) as a model drug, the present study demonstrated a practically feasible process to produce polymeric microspheres for sustained-release delivery of protein drugs with preserved integrity. This process is featured with pre-loading proteins into polysaccharide fine particles via a self-standing aqueous-aqueous “emulsion”, prior to microencapsulation into the microspheres. The protein drug, rhGM-CSF, was partitioned thermodynamically into a dextran dispersed phase of the aqueous-aqueous emulsion, followed by lyophilization and removal of the polyethylene glycol (PEG) continuous phase (using an organic solvent not penetrating into dextran matrix). The harvested dextran particles were then suspended in a dichloromethane solution of polylatic-co-glyclic acids (PLGA) and emulsified in a polyvinyl alcohol (PVA) and NaCl solution of small volume to form embryonic microspheres. The emulsion was then transferred into a NaCl solution of large volume to extract the organic solvent and harden the embryonic microspheres. The obtained rhGM-CSF microspheres showed a satisfied release profile with the day-to-day variation within 9 folds over the multi-weeks long release period. At the same time, the integrity (defined freedom of aggregates measured by SEC-HPLC) and bioactivity (defined by TF-1 cell proliferation) of the proteins were well preserved. The present formulation process ensured good reproducibility and over 89% protein encapsulation efficiency, and practically feasible to adapt to scaled productions.