Abstract: The formulations of pramipexole hydrochloride sustained-release tablets were screened by single factor test and optimized by Box-Behnken design. The effects of the viscosity and content of hydroxypropyl methyl cellulose, as well as the insoluble sustained-release material combined with HPMC K100M on the in vitro release behavior were investigated. After single factor screening, a three-factor, three-level Box-Behnken design was used for optimization using the contents of HPMC K100, Eudragit RSPO and Eudragit L100 as independent variables, and the cumulative release at different time as responses. The optimal range of the three-factor optimized by Box-Behnken design, one of the optimized formulations was achieved with HPMC K100M of 101. 5 mg, Eudragit RSPO of 98 mg, and Eudragit L100 of 13. 7 mg, and the observed responses of the optimized formulation were very close to the predicted values. The in vitro drug release mechanism of the tablet was studied by drug released model fitted with different equations. The results explained that Eudragit RSPO promoted the release of the pramipexole hydrochloride, while Eudragit L100 blocked the release, and there was an antagonism between them. In conclusion, the drug release behavior of optimized formulations prepared by Eudragit RSPO/L100 was stable, less pH-dependent, which improved the drug bioavailability in vivo.