For screening significant variables, Plackett-Burman design was applied to study the reaction of phenol with 2-methycyclohexanol in the presence of perchloric acid as catalyst. A 23 Yates pattern factorial design was used to develop a mathematical model to predict the yield of alkylation of phenol with 2-methycyclohexanol. Analyses of the results revealed that temperature, molar ratio of phenol to 2-methycyclohexanol and amount of perchloric acid were the main effective variables. The critical response was the yield of 2-tert.- methylcyclohexylphenol. The product was characterized by FT-IR spectroscopy, UV-visible spectroscopy and 1H NMR spectroscopy. The adequacy of the suggested model was checked up. The experimental yields exhibited good agreement with the predicted yields designed by the mathematical model and the highest yield obtained was 92.8%.