Microspheres of bovine milk protein casein loaded with progesterone were fabricated by glutaraldehyde cross-linking of an aqueous alkaline solution of the protein dispersed in a hexane and dichloromethane non-aqueous dispersion medium with an aliphatic polyurethane as the stabilizer. Microspheres were characterized for their surface morphology and internal structure using scanning electron microscopy. In vitro release studies in phosphate buffer at 37 degrees C demonstrated that the rate of release of the steroid from the microsphere matrix was a function of cross-linking density, particle size, and drug payload. Microsphere formulations released 50% to 60% of the incorporated steroid in about 30 days and, thereafter, attained a steady state. In the presence of a protein-digesting enzyme such as protease, complete release of the steroid was observed in about 4 days in vitro into phosphate buffer. Intramuscular injection of progesterone-loaded microspheres into rabbits showed a plasma concentration of 1 to 2 ng/mL up to 5 months without any significant burst effect, whereas the powdered steroid administered in saline demonstrated a large burst effect peaking over 20 ng/mL, and the plasma concentration was not sustained beyond 4 days. Data obtained suggest that casein microspheres would be promising as a biodegradable drug carrier for sustained delivery of steroids.