Fluconazole-loaded PLGA microspheres were prepared by the spray-drying process. The influence of some process parameters on the physical characteristics of the microspheres was evaluated. Neither type nor polymer concentration influenced significantly the mean diameter of the microspheres, their size distribution and encapsulation efficiency of the drug. However, the drug loading greatly affected their size and the physical state in which fluconazole can exist in the matrix of the carriers, and, thus, affected the release rate of the drug. Results obtained by differential thermal analysis and X-ray powder diffraction revealed that at low nominal drug loading, fluconazole was incorporated in an amorphous state or in a molecular dispersion in the matrix of the microspheres and at high nominal drug loading part of the drug was in a crystalline form. Release profiles of fluconazole from the microspheres displayed a biphasic shape. The duration and extent of each phase were affected mainly by polymer nature, drug loading and physical state in which fluconazole existed in the polymeric matrix.