The aim of this study was to prepare orally disintegrating tablets (ODTs) containingdexamethasone (DEX) by direct compression method with sufficient hardness and rapiddisintegration time. In order to save time, money, and human resources in designing andimprovement of formulation, the statistical software Design Expert is used. Box–Behnkenresponse surface methodology was applied to evaluate and optimize the effects of concentrationsof three excipients, Kollidon CL-SF (X1), Pearlitol SD200 (X2), and Prosolv SMCC (X3) asindependent factors on four responses: percentage of drug released after 5 min, disintegratingtime, hardness, and friability. Thirteen formulations offered by the Box–Behnken design wereprepared by direct compression method and ultimate weight of 200 mg, while the amount ofDEX was 4 mg. All formulations were characterized for parameters such as diameter, hardness,weight, thickness, friability, and disintegration time. Following the statistical results, the effectsof independent variables on responses were evaluated and the optimum formulation regardingacceptable responses consisted of 15% Kollidon, 39.66% Pearlitol, and 7.5% Prosolv whichshowed 95.28% release of the drug after 5 min, disintegrating time of 30 sec, 6.1 kg hardness,and 0.12% of friability with an acceptable taste as the optimized formulation.