A chemometrics approach has been used to optimize the separation of six quinolone compounds by micellar liquid chromatography (MLC). A Derringer’s desirability function, a multicriteria decisionmaking (MCDM) method, was tested for evaluation of two different measures of chromatographicperformance (resolution and analysis time). The effect of three experimental parameters on a chromatographic response function (CRF) expressed as a product of two sigmoidal desirability functionswas investigated. The sigmoidal functions were used to transform the optimization criteria, resolution and analysis time into the desirability values. The factors studied were the concentration of sodium dodecyl sulfate, butanol content and pH of the mobile phase. The xperimentsweredoneaccording to the face-centered cube central composite design, and the calculated CRF values werefitted to a polynomial model to correlate the CRF values with the variables and their interactions. Thedeveloped regression model showed good descriptive and predictive ability (R2= 0.815,F= 6.919,SE = 0.038,R2CV¼0:791) and used, by a grid search algorithm, to optimize the chromatographic conditions for the separation of the mixture. The efficiency of prediction of polynomial model was confirmed by performing the experiment under the optimal conditions.