Objective To optimize the preparation of Cucurbitacin oral-lipid-nanoemulsion using response surface methodology(RSM).Methods The stability of nanoemulsion was quantitated by KS and KF.The Cucurbitacin oral-lipid-nanoemulsion was prepared by microfluidics.In the central composite design-response surface methodology(RSM-CCD),mean diameter,sterilizing stability and freeze-thaw stability were selected as response variables,RH40%(X1,w/%),SPC%(X2,w/%),MCT%(X3,w/%)were employed as independent variables.The optimal formulation was predicted by response surface methodology.Results The optimal formulation of Cucurbitacin oral-lipid-nanoemulsion could be obtained at 1.15% of RH40,0.5% of SPC and 5.52% of MCT.The mean diameter,sterilizing stability and freeze-thaw stability of the optimal preparation were(113.60±2.10)nm,(2.92±0.70) and(5.14±0.20),respectively.The deviations between measured values and predicted values were not considerable(the maximum deviation was 4.6%).Conclusions The model established by the RSM-CCD method could be used for optimization of the preparation of cucurbitacin oral-lipid-nanoemulsion.