Tolmetin sodium has been investigated and determined from dosage forms as its Cu(II) complex and method optimized by statistical optimization. The assay was developed using two mathematical statistical models: factorial design and response-surface mapping. The decision to apply experimental design techniques to the development of the method was made after a series of screening experiments revealed that the complex formation and extraction are maximized as a function of supporting electrolyte concentration, concentration of Cu(II) acetate and pH of the reaction mixture. One set of two-level three variable factorial experiments was carried out in order to evaluate the main effect, as well as the interaction among factors. The final step was to optimize the values of variables using response surface design. The best set of conditions was selected for further investigation.