Biomass-based energy processes pose logistical challenges because of the dispersed nature of biomass resources. A nationwide supply chain optimization framework is applied to a biomass-to-liquid (BTL) system that uses hardwood biomass resources in the United States to produce gasoline, diesel, and jet fuel. Using optimized BTL refineries of differing capacities (i.e., 0.8, 1, 2.5, and 10 thousand barrels per day) and fuel product ratios (i,e., commensurate with the United States demand, maximization of diesel, and maximization of jet fuel), the supply chain case studies that correspond to the three product ratios are addressed via a large-scale mixed-integer liner programming (MILP) optimization model. The mathematical formulation includes the locations of hardwood biomass in the United States, the delivery locations of fuel products, the transportation costs of every input and output of the refinery, the material balances of each BTL refinery, water resources, and electricity requirement of the supply chain. The framework is also adapted to generate a rank order list of the top 5 locations for each BTL refinery. Solutions of the proposed MILP optimization model provide useful information for the strategic locations of BTL refinery. produce a total of 40 thousand barrels per day of fuels, the allocations of feedstocks and products in the supply chain, and a quantitative basis in evaluating each cost-cotributing factor.