A mixed-integer programming model is developed to assess the economic feasibility of siting a woody biomass-based ethanol facility in the central Appalachian hardwood region. The model maximizes the net present value (NPV) of a facility over its economic life. Model inputs include biomass availability, biomass handling system type, plant investment and capacity, transportation logistics, feedstock and product pricing, project financing, and taxes. Four alternative woody biomass handling systems, which include all processes from stand to plant, are considered. Eleven possible plant locations were identified based on site selection requirements. Results showed that the optimal plant location was in Buckhannon, West Virginia. The NPV of the plant with a demand of 2,000 dry tons of woody biomass per day varied from $68.11 million to $84.51 million among the systems over a 20-year plant life. Internal rate of return (IRR) of the facility averaged 18.67% for the base case scenario. Average ethanol production costs were approximately $2.02 to $2.08 per gallon. Production costs were most impacted by biomass availability, mill residue purchase price, plant investment and capacity, ethanol yield, and financing. Findings suggest that a woody biomass-based ethanol facility in central Appalachia could be economically feasible under certain operational scenarios.