In vitro degradation and drug release of poly (DL-lactide-co-glycolic acid)-methoxypoly(ethyleneglycol) (PLGA-mPEG) microparticles were performed through a dynamic monitoring process, to investigate the effect of degradation on drug release from microparticles and to elucidate the dominant factor that governed the drug release kinetics. Methotrexate (MTX), an antirheurnatic drug, was employed as the model drug. Drug release showed a triphasic pattern: an initial burst release followed by a lag period and subsequently a second burst release. The initial burst release was mainly caused by dissolution and diffusion of drugs at/near the surface of microparticles. During the following lag period, microparticles suffered little morphological changes, whereas the physicochemical changes of the polymer contributed to the increasing mobility of drug molecules, and then provided transport pathways for drug release. Later on, the erosion of the polymer matrix became significant. Morphology study showed that the trend of porosity change was in accordance with last phase release profile, indicating that porosity played an extremely important role in controlling drug release. The liberation pattern of mPEG was elucidated. The more pores formed, the more mPEG chains were exposed to the aqueous medium and disengaged from the polymer. Scanning electron micrography observation further confirmed these conclusions. (C) 2008 Wiley Periodicals, Inc.