In this paper a novel approach is proposed for optimization of electrically serial two-stage thermoelectric refrigeration systems using a chemical reaction optimization algorithm (CRO). In order to investigate the performance of the proposed method, a full computer code was developed and two different test cases with different situations were solved by it to show the accuracy and efficiency of the method. Cooling capacity and coefficient of performance of the thermoelectric refrigeration system are considered as objective functions of the optimization process. The results of the research are compared to those obtained by literature approaches, including analytical and optimization algorithms. The effects of the joint thermal resistance at the interface of the two stages on objective functions in all of the case studies also were studied and sensitivity analysis of COP and cooling capacity of the system to this parameter is conducted. The obtained results showed improvement of the objective functions using the CRO method in comparison to the methods used previously for optimization of the considered refrigeration system. The outlined results revealed that the CRO algorithm can be successfully employed for optimal design of new systems and performance optimization of existence two-stage thermoelectric refrigeration system. (C) 2017 Elsevier Ltd. All rights reserved.