A mixed refrigerant cycle (MRC) has been widely used in liquefaction of natural gas because it is simple and easily operable with reasonable equipment costs. One of the important techniques in MRC is selection of a refrigerant mixture and decision of its optimum mixing ratio. In this work, it is examined whether mixture components (refrigerants) and their mixing ratio influence performance of general MRC processes. In doing this, mixture design and response surface method, which are well-known statistical techniques, are used to find optimal mixture refrigerants and their optimal mixing ratio that minimize total energy consumption of the entire liquefaction process. A MRC process using several refrigerants and various mixing ratios is simulated by Aspen HYSYS and mixture design and response surface method are implemented using Minitab. According to the results, methane (C1), ethane (C2), propane (C3) and nitrogen (N2) are selected as best mixture refrigerants and the determined mixture ratio (mole ration) can reduce total energy consumption by up to 50%.