Etanidazole, a hypoxic radiosensitizer, has potential applications in radiotherapy. Due to its high solubility in water, common methods to encapsulate etanidazole into microspheres are not feasible. In this study, a spray-drying technique was employed to encapsulate etanidazole into the biodegradeable polymer, PLGA65:35. Different fabrication conditions, such as polymer concentration, inlet temperature, feed rate, compressed air flow rate, aspirator ratio, as well as drug-loading were investigated to understand their effects on the particle size and distribution, encapsulation efficiency, and release behaviour. The effect on the morphologies of microspheres were also observed by scanning electron microscopy (SEM) and atomic force microscopy (AFM). It was demonstrated that most of these fabrication conditions influence either the droplet formation process or its subsequent evaporation and particle shrinking process, thereby determining the properties of the microspheres obtained. In many cases, temperature seems to be more important among all the factors considered. The present study demonstrates good fabrication conditions for producing the etanidazole-PLGA65:35-microspheres by using DCM as a solvent. The release of etanidazole from the spray dried PLGA65: 35 microspheres was very fast, with an initial burst of 47% within the first 30 min and a cumulative release of over 80% within the first 5.5 h. The encapsulation efficiency of the drug in the microspheres varied with operating conditions from 69-96%.