A new spinning oil film (SOF) solid-in-oil-in-oil emulsion process was developed to produce uniform-sized proteinloaded biodegradable microspheres. A thin SOF on a cylindrical rotor was used to shear droplets from a nozzle tip to control droplet size. The resulting microspheres with low polydispersity (6%) produced a low burst (6%–11%) release even at high loadings (13%–18% encapsulated solids, 8%–12% protein). The SOF process had a high yield and did not require the presence of water, which can cause protein denaturation, or surfactants, which may be unwanted in the final product. Amorphous protein and crystalline excipient solids were encapsulated into 3 different polymers, giving a homogenous drug distribution throughout the microspheres, and an essentially complete protein encapsulation efficiency (average=99%). In contrast, large burst release was observed for polydisperse microspheres produced by a conventional emulsification technique, particularly for microspheres smaller than 25 μm in diameter, which gave 93% burst at 15% loading. The uniform encapsulation of high loadings of proteins into microspheres with low polydispersity in an anhydrous process is of practical interest in the development of controlled-release protein therapeutics.