The stability of various biodegradable polyester polymers with different molecular weights and lactic/glycolic acids ratios were evaluated in simulated gastrointestinal fluids as an approach to apply microparticles for oral protein delivery on the basis of particle uptake mechanism. A common w/o/w emulsion solvent evaporation technique using dichloromethane for dissolving the polymer and polyvinyl alcohol as the stabilizer was used for encapsulation. Microspheres were incubated at 37C in USP simulated fluids with a concentration of 20 mg mL-1 and also in the literature, which suggested fed or fasted simulated intestinal fluids for different times up to 24 h, while shaking at 75 rpm. The stability assessment was done by detecting pH alterations of the media, enzymatic assay of L-lactic acid, performing differential scanning calorimetric studies and observing the size and morphology of particles. Results showed that the three polymers, namely Resomers R207, RG756 and RG505, could be suitable for the preparation of protein-loaded microspheres.