Refrigeration system holds an important role in chemical/petrochemical processes. The traditional cascade refrigeration system (CRS) used in ethylene plants contains multiple refrigerants working at multiple temperature/pressure levels. In this study, a general methodology is developed for the optimal process synthesis of a CRS based on exergy analysis. This procedure involves four stages: (1) refrigeration system exergetic analysis; (2) optimization model development for simultaneous synthesis of refrigeration system and heat exchanger network (HEN); (3) HEN configuration; and (4) final solution validation. The exergy-temperature chart is used to comprehensively analyze a CRS. A mathematical model is presented to minimize total compressor shaft work of the HEN-considered CRS, where multiple recycling loops satisfying all cooling/heating demands are simultaneously addressed. The optimal solution is examined by rigorous simulations to verify its feasibility and consistency. The efficacy of the developed methodology is demonstrated by a case study of a propylene CRS in an ethylene plant. (c) 2015 American Institute of Chemical Engineers AIChE J, 61: 2471-2488, 2015