Eight kinds of self-catalyzed poly(ortho-esters) (POEs) are used to fabricate bovine serum albumin (BSA)-containing microspheres using a W/O/W double-emulsion solvent extraction/evaporation method. All eight kinds of POE polymers used in this study are shown able to form microspheres under proposed fabrication conditions. The surface morphology and inner structure of the microspheres are analyzed using scanning electron microscopy (SEM). The microspheres have a size range from 64.7 to 120.2 mum. POE with a higher viscosity leads to bigger microspheres. It was found that the POE composition has a significant effect on BSA release profiles. POEs, which are more hydrophilic and contain a greater amount of glycolide or lactate (latent acid), yield higher BSA release rates. Specifically, POE containing 1,6-hexanediol diglycolide (HD-diGL) microspheres have the highest BSA release rate after a 20-day test through a combination of surface erosion and diffusion mechanisms. POE containing a high percentage of the trans-cyclohexanedimethanol (CDM) segment tends to yield microspheres with a lower release rate because of its hydrophobic nature. It was also found that the BSA release rate is more rapid at 37 degreesC than at 22 degreesC because of faster polymer degradation and water penetration at 37 degreesC. Experimental results suggest that various protein release rates can be achieved by using different compositions of POEs.