An optimization-based supply chain framework is proposed for the nationwide, regional, and statewide analyses of natural gas to liquids (GTL) systems for the United States. With optimized GTL refineries of differing capacities (i.e., 1, 5, 10, 50, and 200 thousand barrels per day) and fuel product ratios (i.e., unrestricted, maximization of diesel, maximization of kerosene, and commensurate with the United States demand), the optimal nationwide, regional, and statewide supply chains are obtained by solving a large-scale mixed-integer linear optimization (MILP) model that minimizes the total cost of fuel production. The mathematical formulation includes the locations of natural gas in the United States discretized by county, the delivery locations of fuel products, the transportation costs of every input and output of the refinery, the material balances of each GTL refinery, water resources, electricity requirements/production of the supply chain, and the CO 2 sequestration capacities in the United States. The solutions of the proposed MILP optimization model provide useful information for the strategic locations of GTL refineries, the allocations of feedstocks and products in the supply chain, and a quantitative basis for evaluating each cost-contributing factor. Comprehensive analyses of the effects of modifying the geographical scope of the supply chain problem are completed, and the economic performances of GTL supply chains in different regions are compared. The results suggest that GTL supply chains can produce highly competitive liquid fuels in the United States and that the Southwest and Central regions of the United States would be the most profitable areas for these supply chains.