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In this paper, we analyze and compare the performance of the vertical and the horizontal automated-guided-vehicle transportation systems. We use results in queuing network theory and a transportation simulator to design a hybrid strategy for this study, and to set the appropriate number of agents in the systems. Next, these two transportation systems are evaluated based on cost-effectiveness criteria. For this purpose, the total construction costs of the systems for the various transportation demands are compared. Finally, we provide analytical results to evaluate and to obtain the most efficient system, based on the validity of each system, under different demand scenario. Note to Practitioners-A good design methodology is essential for the study of the optimal layout in an automated container terminal. Port designers need to select the most efficient automated-guided-vehicle (AGV) transportation system, and to set the appropriate number of agents operating in the system. This study presents a hybrid design methodology and a cost-effectiveness comparison of the vertical and the horizontal transportation systems. Our proposed design methodology is able to derive the combinatorial optimal design solutions rapidly, and at the same time pin point the bottleneck in the system. This proposed methodology can be easily applied to any transportation or logistics system, provided the system can be divided into components represented as nodes in a graph. Our results demonstrate that the horizontal AGV transportation system is more effective than the vertical AGV transportation system under most demand scenarios.