Preformed porous microspheres of poly(L-lactic acid) (Accurel(R)) have been shown to sustain the release of highly water soluble solutes, like dextran and mannitol, for a time period of more than 4 months. The purpose of this investigation was to mechanistically characterize the release of a model protein, bovine serum albumin (BSA), from these highly porous microspheres. The microspheres were loaded with [C-14]BSA in three different concentrations of 0.06, 0.26 and 0.59% w/w. The rate of release of [C-14]BSA from microspheres was correlated to media ([H-3]PBS) uptake. The release of BSA showed a biphasic pattern; an initial rapid release, followed by a sustained release. The initial burst of BSA was found to be inversely proportional to BSA loading and highly correlated to water penetration. The sustained release phase was independent of water penetration kinetics. Washing the microspheres did not remove either the surface bound BSA or the BSA incorporated in the microsphere matrix, indicating the tight binding of BSA to highly porous microspheres. Furthermore, addition of a surfactant induced a dramatic increase in the amount of BSA released, suggesting that the release is controlled by the surface binding of BSA to the polymer. Also, the release rate of BSA beyond the initial burst was found to be much slower than for the lower MW macromolecules like dextran at a similar level. The data from the present work suggests the BSA-polymer interaction to be a major contributing factor in explaining the overall BSA release kinetics.