To optimize and predict the release of proteins from biodegradable microspheres based on crosslinked dextran, a fundamental understanding of the mechanisms controlling their release is necessary. For that purpose, a mathematical model has been developed to describe the release of proteins from these hydrogel-based microspheres. A kinetic Monte Carlo scheme for the degradation of a small domain inside the microsphere was developed. The results from this were used in a second kinetic Monte Carlo scheme to model the diffusion and the subsequent release of proteins. The only processes included in this model are diffusion and degradation. The general effects of diffusion, crosslink density, protein loading, and clustering of proteins on the release were investigated. The model crosslink density (Xmodel) and the model diffusivity (Dmodel) were fitted to experimental release data of BSA monomer from hydroxyethyl methacrylated dextran (dex-HEMA) microspheres. By using the experimental release curves of liposomes and BSA monomer, it was found that (1) the model crosslink density (Xmodel) scales with the hydrodynamic diameter (dh) as dh(1.64) and (2) the diffusivity of the protein (Dmodel) scales approximately with 1/dh (Stokes-Einstein). Using these scaling relations, quantitative predictions of the release curves of BSA dimer, immunoglobulin G and human growth hormone were possible. In conclusion, this model may play an important role in the optimization, understanding and prediction of the release of various proteins from degradable hydrogels.