Biodegradable microspheres such as those made of poly-D,L-lactide (PDLLA) are widely investigated delivery systems for drugs or antigens. The aim of this study was to examine experimental conditions in order to produce PDLLA microspheres with the best properties for controlled and sustained drug delivery by the modified precipitation method. For this purpose, the following parameters were varied: co-solvent (methanol or ethanol), the concentration of stabilizer polyvinyl alcohol (PVA), chloroform-to-water ratio and the speed and time of homogenization. Scanning electron microscopy (SEM) and stereological analysis were used to characterize the particles. The average size and morphology of the microspheres varied substantially with preparation conditions from 8.44–1.25 μm. Results showed that the smallest particles were obtained with methanol, 1% PVA and with 10 min of homogenization at 21,000 rpm. Microsc. Res. Tech., 2008. © 2007 Wiley-Liss, Inc.