The objective of the present research was to study the effect of two different types of polymer such as HPMCK4M and Eudragit RS 100 in formulation of a sustained release (SR) matrix tablet of stavudine. Stavudine and polymer compatibility studies were performed using Fourier transform infrared spectroscopy (FT-IR) and Differential scanning calorimetry (DSC). The pre-compression mixture formulation was evaluated for flowability and compressibility. The tablets were prepared by direct compression method. The effect of concentration and type of polymer on In-vitro drug release and release kinetics was studied extensively. The optimized formulation was subjected to stability testing. FT-IR and DSC studies revealed no interaction between stavudine and polymers. Flowability and compressibility study of pre-compression powder formulation showed that these formulations were within the theoretical range for processing into tablet dosage form. In-vitro release studies exhibited that the drug release was sustained up to 12 h for SR matrix tablets prepared with HPMCK4M whereas EudragitRS100 based SR matrix tablets could not sustain the release for more than 6 h. Incorporation of PVPK90 as a dry binder assisted in maintaining matrix integrity of Eudragit RS100 based SR matrix tablet and sustained the release up to 12 h. Stability studies showed no significant change in drug content for both strip packed and unpacked tablets. Hence both type of polymers mentioned above can be used for the preparation of SR matrix tablets of stavudine. Keywords: HPMCK4M, Eudragit RS100, PVPK90, In vitro drug release