The objective of this study was to formulate and evaluate the drug-polymer interaction of Didanosine using two polymers with different characteristics as Ethyl cellulose or Cellulose acetate phthalate. Microspheres were prepared by the emulsion solvent evaporation. The effect of drug-polymer interaction was studied for each of microspheres. Important parameters in the evaluation of a microencapsulation technique are encapsulation efficiency, yield production, particle size, surface characteristics of microspheres, scanning electronic microscopy (SEM), powder X-ray diffraction analysis (XRD) and differential scanning calorimetry (DSC). The in-vitro release studies are performed in buffer (pH 7.4). Microspheres containing cellulose acetate phthalate and Ethyl cellulose showed 80-87% and 75-79% of entrapment efficiency, respectively. The thermogram X-ray and DSC showed stable character of Didanosine in the microspheres and revealed an absence of drug polymer interaction. The prepared microspheres were spherical in shape and had a size range of 355 μm for Cellulose acetate phthalate microspheres and 345- 383 μm for Ethyl cellulose microspheres. The results suggest that Didanosine was successfully and efficiently encapsulated; the release rates of matrix microspheres are related to the type of polymer, only when formulation (FDEC3) used to get prolonged drug release with increasing the polymers content in the microspheres. Data obtained from in-vitro release for microspheres were fitted to various kinetic models and the high correlation was obtained in the First order model.