Drug release from poly(lactide-co-glycolide) (PLGA) microspheres is strongly determined by the pore structure of the particles. This study examines how swelling-induced pore constriction delays the drug release and by which factors this process is controlled. Combination of different porosimetric and pycnometric methods enabled insight into the submicroscopic range of the pore structure and revealed that remarkably the polymer free volume plays a crucial role in drug release from PLGA microspheres. Surprisingly, the latter was shown to be inversely correlated to the degree of diffusional drug release. This can be explained by a swelling-induced constriction of the macroporous channel system in the microspheres which is related to the availability of free volume. The hole free volume was shown to be well controllable by the manufacturing conditions. Thus, the study deepens comprehension of the mechanism of drug release from biodegradable microparticles and offers an effective approach for controlling the release behavior. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 39740.