In present study, an attempt was made to design sustained-release tablets containing Didanosine. Formulation of Didanosine matrix tablet was prepared by the polymer combination in order to get required theoretical release profile. Influence of natural polymer on Didanosine was studied. The prepared tablets were selected for DSC and FTIR studies. The tablets were selected for DSC and FTIR studies did not show any chemical interaction between drug and polymer. The values of pre-compression parameters of prepared granules were evaluated the results were within prescribed limits and indicated good free flowing property. The hardness of the tablets ranges from 5.9 to 6.1 kg/cm2. Friability is less than 1%, indicated that tablets had a good mechanical resistance. Weight variation test revealed that the tablets were within the range of pharmacopoeial limit. Thickness of the tablets was ranges from 4.71 to 5.08 mm.. All the evaluation parameters were within acceptable range for all the formulations. The drug content of the tablets was ranges from 96 % to 99%. Thickness, hardness and drug content were within the range of pharmacopoeial limit. The evaluation parameters were within acceptable range for all the formulations. In-vitro release profile was check for 12 hrs to evaluate the SR matrix tablet of Didanosine. The optimized tablets were carried out according to ICH guidelines at 40 ± 2º C/ 75 ± 5% RH for three months. All the prepared tablets were stable at room temperature. Among all the 12 formulations the formulation WGXG-3, WGGK-6 and WGXK-10 shows maximum release within 12 hrs are considered as best formulations. So, it may be concluded that sustained release matrix tablets would improve the patient compliance and bioavailability may be improved by polymer combination.