Poly(dl-lactic)acid-methadone base microspheres able to release the drug over 7 days have been developed using the solvent evaporation method and an optimization strategy. The first optimization step involved in vitro release study of nine different formulations elaborated in agreement with a composite rotable second order experimental design. Polymer degradation was observed during microsphere preparation; degradation index, defined as the number of broken bonds in relation to the initial number of polymer molecules, was less than 0.72 for weight average molecular weight (Mw) below 145 000 and 0.93 for 198 000 Mw. Degradation index ranging between 1.4 and 6.54 were observed during in vitro release assay. Specific surface determinations show larger than expected values from the number-volume average diameters, and DSC studies showed that methadone is dissolved to a limited extent. Once the region of interest was located, two new formulations were prepared and tested. Optimum formulation released 18.6% of drug content over the first 24 h, against a targeted value of 14.3% for a near zero order release rate over 7 days, and 68.0% after 7 days.