The aim of this study was to obtain biodegradable indomethacin microspheres for intra-articular administration in rheumatoid arthritis, where angiogenic processes are involved. Indomethacin concentrations to achieve an anti-angiogenic effect would be five-times higher than an antiinflammatory. Microspheres were prepared by solvent evaporation using PLGA. Indomethacin is a poor water-soluble drug with it being possible that dissolved and non-dissolved drug co-exist within the polymeric matrix resulting in rapid release. To control this release, an oil-PEG-derivative was incorporated, producing changes in morphology, crystallinity and indomethacin release. To minimize the amount of microspheres administered, a two-factor five-level central rotable composite 2(2) + star design was employed with two independent variables: indomethacin percentage and PEG-derivative percentage. The optimum formulation showed mean encapsulation efficiency of 94.3 +/- 2.2% and released 7.99 +/- 0.25 mu g indomethacin/day/mg microspheres for 21 days. A dose of 20-50 mg of this formulation could be appropriate to achieve both anti-angiogenic and antiinflammatory effects. Preliminary cytotoxicity studies performed in rat splenocytes showed an adequate cell viability.