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This paper investigates the effect of sodium hexametaphosphate (SHMP) depressant/dispersant in the presence of methyl isobutyl carbinol (MIBC) frother and soluble starch (SS) depressant on the flotation kinetics of talc ore. Emphasis is on a comparison between the evaluation of a custom design of experiment (DoE) using the multilinear regression analysis (MRA) and response surface methodology (RSM) approach. Although analysis of variance (ANOVA) is a good first step in the evaluation of the effect of factors on froth flotation processing, it nonetheless only reveals the effects that are the same under all conditions. In the case of SHMP, its effect on separation efficiency is positive; however, if it is used along with SS, the effect is negative. Moreover, if a higher frother dosage is used, the effect of SHMP on separation efficiency is negligible.