Polymer degradation and drug release kinetics from PLGA microspheres were investigated under neutral and acidic pH conditions. Two different Mw formulations (Mw: 25,000 and 70,000) were investigated and both exhibited a triphasic release profile at pH 7.4 as well as at pH 2.4. The initial burst and lag phases were similar for both pH values, while the secondary apparent-zero-order phase was substantially accelerated at pH 2.4. The polymer molecular weight change with time for the microspheres followed first order degradation kinetics for both pH values. A linear relationship was established between % drug release (post burst release) and Ln (Mw) for both pH conditions. Most significantly, morphological studies showed that the mechanism of polymer degradation changed from "inside-out" degradation at pH 7.4 to "outside-in" at pH 2.4. At pH 7.4, the microspheres followed the usual morphological changes such as surface pitting and pore formation. Whereas, at pH 2.4 the microspheres maintained smooth surfaces throughout the degradation process and were susceptible to fracturing. The fracturing of the microspheres was attributed to crystallization of oligomeric degradation products as a consequence of their low solubility at this pH. It also appeared that degradation occurred in a more homogeneous pattern at pH 2.4 than is typical of PLGA microspheres at pH 7.4. This may be a result of the entire microspheres experiencing a close-to-uniform pH at 2.4. However, at pH 7.4, the local micro-environmental pH within the microspheres has been reported to vary considerably due to a build up of acid oligomers. This heterogeneous degradation results in the random formation of channels within microspheres degraded at pH 7.4 which was not observed in those degraded at pH 2.4. This is the first time that morphological changes during PLGA microsphere degradation have been compared for low and neutral pH and the data shows a change in the mechanism of degradation at the low pH.