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This paper presents a novel mathematical model of a closed-loop layout problem with unequal-sized facilities. This type of problem belongs to a class of combinatorial optimization, and NP-hard problems due to its complexity and high volume of computation. Obtaining an optimal solution for this complex, large-sized problem in reasonable computational time by using traditional approaches and optimization tools is extremely difficult. Thus, a meta-heuristic algorithm based on a genetic algorithm (GA) is proposed to solve the closed-loop layout problem. This proposed GA reports near-optimal and promising solutions in short period of time because of its efficiency. In this paper, a local search, based on 2-Opt algorithm, is also employed to improve the solutions obtained by the proposed GA. Finally, the computational results obtained by this algorithm are analyzed and compared with the results reported by the Lingo 8.0 software package.