Plackett-Burman experimental design was applied for screening significant variables influencing the yield of alkylation of p-chlorophenol with methylcyclohexanol in the presence of sulfuric acid. Analyses of the results revealed that temperature, molar ratio of p-chlorophenol to methylcyclohexanol, and amount of sulfuric acid were the main effective variables. The influence of individual effects of these variables and their interactions on experimental response were analyzed by applying fractional factorial design. Finally, a mathematical model was developed to predict the yield of alkylation of p-chlorophenol with methylcyclohexanol in the presence of sulfuric acid under any reaction condition. The experimental yields showed good agreement with the predicted yields calculated by the mathematical model.