Objective: Cisapride is a novel prokinetic agent is best candidate for GERD. Cisapride 20 mg can be given thrice in a day given along with Proton pump inhibitor. By developing the sustain release formulation of Cisapride, the frequency of both drug can be reduce to once only to obtain good therapeutic response. Methods: Cisapride SR Tablets were prepared by direct compression technique with HPMC K4M and HPMC K100M polymers. Followed by various evaluation tests including in vitro disintegration and dissolution, the formulation was optimized by 32 full factorial designs with drug release kinetic analysis, compatibility studies (FTIR) and stability studies. Results: Results of Preformulation studies of the Cisapride indicate that it has poor flow property and compressibility property. To improve the flow and compressibility property, it was beneficial to use the directly compressible grade components in the formulation of tablet. Results of DSC study shown that there is no change in drug’s melting peak after the preparation of tablet. Hydrophilic matrix of HPMC K4M and HPMC K100M in combination sustained the Cisapride release effectively for more than 12h. The result indicates that the combination of HPMCK4M and HPMCK100M can be successfully, On the basis of the preliminary trials in the present study a32 full factorial design was employed to study the effect of independent variables, i.e. concentration of HPMCK4M(X1) and concentration of HPMCK100M(X2)on dependent variables like% drug release Q2, Q6 and Q10. Drug release is also dependent on the size of matrix tablets so, size and surface area was kept constant. Factorial batches F018, F019, F020, and F021 give the f2 value 75-100. Factorial batch F019 gives the highest f2 value 86.04 and also all the hour’s drug release was within the specified limits. Conclusion: The prepared formulation of Cisapride sustains release matrix tablet was stable and effective in treatment.