Based on single factor experiments, a three level, four variable central composite designs were carried out to establish a quadratic regression model for the catalytic synthesis of isoamyl isovalerate over sulfonated organic heteropolyacid salts as a function of molar ratio of alcohol to acid, reaction time, the amount of water-carrying agent and the amount of catalyst. The optimum conditions were obtained as follows: n (isoamyl alcohol): n (isovaleric acid) = 1.1:1, amount of catalyst was 6.4% of acid, reaction time 2 h and water-carrying agent 10 mL. Under these conditions, the yield of isoamyl isovalerate reached 97.5%. The ionic liquid could be reused six times without noticeable drop in activity. Under optimum conditions, catalysts showed a superior catalytic efficiency and reusability due to better superacidity, lower molecular transport resistance and self-separation characteristics.