Dexamethasone-loaded poly(lactide-co-glycolide) (PLGA) devices are commonly used as model systems for controlled release. In this study, PLGA nanoparticles containing dexamethasone acetate were prepared by a nanoprecipitation technique in the absence of organochlorine solvents and were characterized by their mean size, ζ potential, scanning electron microscopy, and differential scanning calorimetry to develop a controlled release system. The analytical method for the quantification of dexamethasone acetate by high-performance liquid chromatography was validated. The results show that it was possible to prepare particles at a nanometric size because the average diameter of the drug-loaded PLGA particles was 540 ± 4 nm with a polydispersity index of 0.07 ± 0.01 and a ζ potential of −2.5 ± 0.3 mV. These values remained stable for at least 7 months. The drug encapsulation efficiency was 48%. In vitro tests showed that about 25% of the drug was released in 48 h. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 41199.