Itopride HCl is a novel prokinetic agent. It is used mainly in gastroesophageal reflux disease. The objective of this investigation was to formulate sustained release matrix tablets of Itopride HCl using different polymer and polymer combinations to prolong the drug release over 12 hours hence improve patient compliance and minimize side effects. The tablets of Itopride HCl were prepared using different cellulosic polymers and methacrylate copolymers (Eudragits) in various ratios. The in-vitro drug release was carried out using the pH shift method. Optimization of polymer concentration that controls the drug release was performed. Bioavailability study on rabbits was performed to investigate the rate and extent of Itopride HCl absorption from the optimum formulated tablet compared to that of commercial immediate release tablets (Ganaton®). The drug release was found to depend upon the polymer type and concentration. Sustained release tablets containing either hydroxypropyl methyl cellulose or Eudragit RSPM in 1:3 (drug: polymer, weight ratio) gave the most sustaining effect among the single polymers. The drug release rate from tablets prepared using polymer combinations is slower compared to that from matrices containing single polymers. Tablets containing drug, hydroxypropyl methylcellulose and Eudragit RSPM in weight ratio of 1:1:3 gave the slowest drug release rate. The time for reaching peak plasma concentration (Tmax) and the area under the curve from zero to 24 h AUC(0– 24) were higher following formulated tablet administration compared to the marketed tablets. The percentage relative bioavailability of Itopride HCl from the selected formula was found to be 129%.