This paper reports how poly(DL-lactide) microspheres of different molecular weight and BSA content were manufactured in order to evaluate the influence of these two variables on the protein release profile, using a composite central rotational design. The microspheres were prepared by a double emulsion method using different w/o phase ratios. The BSA encapsulated was about 80% of the theoretical amount incorporated. The resulting microspheres proved porous except for three batches. The release of BSA from microspheres presented two phases, first a high burst effect ranging from 37.3 to 75% of the protein incorporated, and a second slower one. Analysis of the release results clearly shows a positive linear dependence of the slope of the slow release phase on the molecular weight of polymer, due most likely to the formation of hydrogen bridges between the terminal -OH groups of the polymer chains and the solitary pairs of donor atoms of the protein. Non-porous microspheres with a lesser burst effect were obtained by decreasing the w/o ratio of the first emulsion during the preparation process.