The aim of this study was to better understand the mass transport mechanisms controlling drug release from PLGA microparticles. New insight was gained based on the experimental monitoring of single microparticle swelling. An oil-in-water (O/W) solvent extraction/evaporation method was used to prepare ketoprofen-loaded microparticles, varying the initial drug loading from 0.6 to 45.2%. Importantly, the microparticle size was kept about constant. At low ketoprofen loadings, the release patterns were clearly tri-phasic: an initial burst release was followed by a period with an about constant release rate and a final (again rapid) drug release phase. With increasing initial drug content the onset of the third release period was shifted to earlier time points. At even higher drug loadings, the release patterns became more or less bi- or mono-phasic. Interestingly, all types of microparticles showed substantial swelling after a lag-time, which coincided with the onset of the third (and again rapid) drug release phase at low loadings and proceeded it by 1 or 2d at higher drug loadings. The substantial microparticle swelling set on as soon as a critical PLGA molecular weight was reached (around 20kDa). Thus, the onset of the third drug release phase from the PLGA microparticles might be explained as follows: once the macromolecules are sufficiently short, substantial amounts of water penetrate into the system, significantly increasing the mobility of the drug within the microparticles and resulting in increased drug release rates.