The purpose of this research was to prepare and evaluate a non-bitter donepezil hydrochloride (DH) orally disintegrating tablet (ODT) for enhanced patient compliance. Taste masking was done by preparing microspheres with different ratios of drug and Eudragit EPO using spray drying method. The entrapment of the drug into microspheres was confirmed by scanning electron microscope (SEM) and X-ray powder diffraction. It was found that microspheres with a drug-polymer ratio of 1 : 2 could mask the taste obviously by inhibiting the release of DH in simulated salivary fluid. Microspheres-loaded tablets containing Polyplasdone NF and Low substituted Hydroxypropyl Cellulose (L-HPC) both at a 10% level showed rapid disintegration, in vitro (15.5 s) and in vivo (19.8 s), which were faster than that of marketed tablets (36.7, 41.3 s, respectively). Results from taste evaluation in human volunteers revealed that the ODTs with taste-masked microspheres had significantly enhanced palatability. Dissolution in vitro and pharmacokinetics in rats were evaluated for the tested ODTs compared to the donepezil hydrochloride commercial product (ARICEPT). Both tablets showed comparable dissolution patterns in vitro and similar area under curve from 0 to 24 h (AUC(0-24)), C(max) and T(max) of DH in vivo to each other, suggesting that the tested ODTs might give the similar drug efficacy in rats compared to that of ARICEPT. Thus, it was concluded that DH ODTs with masked taste were obtained by Eudragit EPO-based microspheres, drug loaded microspheres neither decreased the bioavailability nor delayed the release of DH.