A new approach for the incorporation of safety criteria into the selection, location, and sizing of a biorefinery is introduced. In addition to the techno-economic factors, risk metrics are used in the decision-making process by considering the cumulative risk associated with key stages of the life cycle of a biorefinery that includes biomass storage and transportation, process conversion into biofuels or bioproducts, and product storage. The fixed cost of the process along with the operating costs for transportation and processing as well as the value of the product are included. An optimization formulation is developed based on a superstructure that embeds potential supply chains of interest. The optimization program establishes the tradeoffs between cost and safety issues in the form of Pareto curves. A case study on bio-hydrogen production is solved to illustrate the merits of the proposed approach. (c) 2013 American Institute of Chemical Engineers AIChE J, 59: 2427-2434, 2013