Abstract: OBJECTIVE To optimize the formulation of butoconazole nitrate sustained-release cream by the central composite design-response surface method (CCD-RSM). METHODS In the formulation design using CCD-RSM, independent variables were the amounts of liquid paraffin and emulsifier, the ratio of auxiliary emulsifier in the emulsifiers. The percentages of in vitro cumulative releases at 24, 48, 72 h were dependent variables. Multilinear and quadratic models were used to estimate the relationship between the dependent and the independent variables, and to delineate RSM and overlay contour plots in order to select the optimal formulations. RESULTS Quadratic model showed better prediction capability than multilinear model. The quantitative relationships between three factors and three evaluation indexes were characterized. Moreover, in vitro release test of one selected optimal formulation indicated that were high approximation between the observed and estimated values. CONCLUSION The CCD-RSM can be applied to optimize the formulation of butoconazole nitrate sustained-release cream and the established model is of satisfactory predictive value.