In vitro drug release and degradation mechanism of Poly (dl-lactide-co-glycolic acid)- methoxypoly (ethyleneglycol) (PLGA-mPEG) microparticles were investigated under different pH conditions. Methotrexate(MTX), an antirheumatic drug, was employed as the model drug. In polyester-based microparticle system, two main issues involved in degradation were water uptake and the carboxylic groups produced by chain scission. Polymer composition was identified to be responsible for the odd degradation behavior in different releasing media. Because of the exposure of mPEG chains at the particle surface, microparticle degradation showed apparent different mechanism under the investigated releasing conditions. At pH 10.08, microparticles exhibited rapid weight loss but slower molecular weight decrease, and the degradation pattern was close to surface degradation. At pH 7.4, micro-particles underwent heterogeneous bulk degradation. However, at pH 1.2, it showed fastest molecular weight decrease while slowest weight loss, and homogeneous degradation was observed. Particle agglomeration was also seen in acidic environment. Fourier transform infrared (FTIR) spectrum results indicated the crystallization of drugs under the low pH condition. Drug release was dependent on transport paths and drug property. These two factors were highly controlled by the polymer degradation and drug solubility in the releasing media as well as drug crystallinity. (c) 2008 Wiley Periodicals, Inc.