The objective of this work was to use a full factorial design and response surface methodology to optimize and prepare fast disintegrating tablets of Itopride hydrochloride (ITOHCl). Tablets were prepared by direct compression technique and evaluated for their drug content, weight variation, hardness, friability, wetting, disintegration time, and in-vitro release. In addition, the optimum formulation was evaluated for taste, mouth feel and in-vivo disintegration time in human volunteers. A 32 full factorial design was employed to evaluate different variables affecting ITOHCl tablets. Furthermore, The response surface methodology was used to analyze the effect of the total amounts of superdisintegrant (SD, X1) and the percentage of sodium starch glycolate (% SSG) in the total amounts of superdisintegrant (SSG, X2) on the % friability (Y1), Disintegration time (Y2) and ITOHCl released after 10 mins (Y3). The increase in the (SD, X1) led to an increase in the % friability while an increase in % SSG led to a decrease in the % friability. The (SD, X1) were found to have a positive influence on the disintegration time, whereas the % SSG had a non-significant effect on the disintegration time. In addition, the release of ITOHCl from different formulations was affected by both (SD, X1) and the percentage of SSG. The optimized formulation showed in-vivo disintegration time comes in accordance with the in-vitro data and has a good mouth feel and bitter taste masking character compared with commercial ITOHCl tablets.