Abstract：Objective Optimization of the matrix tablets prescription of doxifluridine by the response surface method, and to research mechanism of in vitro release. Methods Hydroxypropyl methylcellulose (HPMC K4M) was used as the matrix material, using the method of direct tableting in combination with other materials for preparing the matrix sustained-release tablets of doxifluridine. The drug released mechanism of the tablets were studied by the model-fitting of drug release with different equations and the Box-Behnken design-response surface methodology was applied to optimize the formulation. Results Optimized the matrix sustained-release tablets of doxifluridine had a good performance in vitro release. It achevied sustainable release for 24h, and the drug release was in line with the ritger-peppas model. Conclusion The model established by the Box-Behnken response surface methodology can be used to optimize the prescription of the matrix sustained-release tablets of doxifluridine which achieved the design requirements.