The dispersion of non-steroidal antiinflammatory drugs (NSAIDs) into biodegradable polymeric matrices have been accepted as a good approach for obtaining a therapeutic effect in a predetermined period of time meanwhile minimizing the side effects of NSAIDs. In the present study, it was aimed to prepare Naproxen Sodium (NS), (a NSAID) loaded microsphere formulation using natural Bovine Serum Albumin (BSA) and synthetic biodegradable polymers such as poly(lactide-co-glycolic acid) (PLGA) (50:50 MW34 000 and 88 000 Da) for intra-articular administration, and to study the retention of the drug at the site of injection in the knee joint. NS incorporated microspheres were evaluated in vitro for particle size (the mean particle size; for BSA microspheres, 10.0 +/- 0.3 mum, for PLGA microspheres, 9.0 +/- 0.2 and 5.0 +/- 0.1 mum for MW 34 000 and 88 000 Da, respectively), yield value, drug loading, surface morphology and drug release. For in vivo studies, monoarticular arthritis was induced in the left knee joints of rabbits by using ovalbumin and Freund's Complete Adjuvant as antigen and adjuvant. A certain time (4 days) is allowed for the formation of arthritis in the knee joints, then the NS loaded microspheres were injected directly into the articular cavity. At specific time points, gamma scintigrams were obtained to determine the residence time of the microspheres in knee joints, in order to determine the most suitable formulation. This study indicated that PLGA, a synthetic polymer, is more promising than the natural type BSA microspheres for an effective cure of mono-articular arthritis in rabbits.