Refrigeration system holds an important role in process industries. The optimal synthesis cannot only reduce the energy consumption, but also save the production costs. In this study, a general methodology is developed for the optimal design of refrigeration cycle and heat exchanger network (HEN) simultaneously. Taking the heat integration between the external heat sources/sinks and the refrigeration cycle into consideration, a super-structure with sub-coolers is developed. Through defining logical variables that indicate the relative temperature positions of refrigerant streams after sub-coolers, the synthesis is formulated as a Generalized Disjunctive Programming (GDP) problem based on LP transshipment model, with the target of minimizing the total compressor shaft work in the refrigeration system. The GDP model is then reformulated as a Mixed Integer Nonlinear Programming (MINLP) problem with the aid of binary variables and Big-M Constraint Method. The efficacy of the process synthesis model is demonstrated by a case study of ethylene refrigeration system. The result shows that the optimization can significantly reduce the exergy loss as well as the total compression shaft work. (c) 2017 The Chemical Industry and Engineering Society of China, and Chemical Industry Press. All rights reserved.