To investigate the effect of polymer molecular weight (MW) on rhBMP-2 delivery by thermoreversible polymers, four polymers with similar lower critical solution temperatures (20 degrees -22 degrees C) but different MWs were studied. Thermoreversible polymers were based on N-isopropylacrylamide (NiPAM), ethyl methacrylate (EMA), and N-acryloxysuccinimide (NASI), and had MWs of either approximately 49 kDa or approximately 400 kDa. The NASI content was either 0 or 1-1.6%. High MW polymers, irrespective of their NASI content, formed a stable gel with significantly lower water uptake and exhibited a dense micelle with average pore size smaller than the low MW polymers. NiPAM/EMA polymers without NASI did not conjugate with recombinant human bone morphogenetic protein-2 (rhBMP-2). NiPAM/EMA polymers containing NASI, however, gave conjugation with rhBMP-2. For polymers without NASI, a high MW was essential for rhBMP-2 retention when injected intramuscularly in Sprague-Dawley rats. For NASI-containing polymers, the MW of the polymer did not make a significant difference because rhBMP-2 retention was equivalent for different size polymers. We conclude that polymer MW affects rhBMP-2 retention in vivo in polymers designed for physical entrapment of rhBMP-2, but not in polymers designed for chemical conjugation with rhBMP-2.