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The objective of this investigation was to prepare orodispersible tablets (ODTs) of ondansetron HCl using a direct compression method. A combination of glycine and chitosan was used as a disintegrating system and these tablets were compared for mechanical strength and disintegration time with those containing superdisintegrants. The Plackett-Burman screening design was used to screen the independent variables [concentration of glycine (X(1)), concentration of chitosan (X(2)), concentration of ondansetron HCl (X(3)) and tablet crushing strength (X(4))] which were found to actively influence the dependent variables [disintegration time in the oral cavity (DT), wetting time (WT), and water absorption ratio (WAR)]. Further, a central composite design was used to formulate additional ODTs of ondansetron HCl for estimating response in the extended spherical domain. The regression analysis (performed using Statistica-7.0) of quadratic fit revealed that DT or WT and WAR were 99% and 98% correlated with active factors (X(1), X(2) or X(3)), respectively. The data showed that disintegration time of optimized ondansetron HCl ODTs was not significantly different (p<0.05) from ODTs prepared using Croscarmellose sodium or Crospovidone.