By-product synergy (BPS) is an industrial ecology practice that involves utilization of industrial by-products as feedstocks for other industrial processes. A novel decision support tool is developed to analyze BPS networks that involve material processing and transport among regional clusters of companies. Mathematical programming techniques are used to determine the optimal network design and the material flows that minimize total cost or environmental impacts. This methodology is incorporated into a graphical software package called Eco-Flow™. The tool has been applied to model and analyze available synergies in an existing BPS network centered in Kansas City, Missouri. A base case, which assumes no synergies, is compared with the optimal BPS solution found by Eco-Flow™. The results for Kansas City suggest that when companies in the network cooperate to optimize the system profitability, up to $15 million per year of savings are possible. The findings also indicate that the BPS approach would result in 29% reduction in total cost, 25.8% reduction in average company cost, 30% reduction in carbon dioxide (CO2) emissions, and 37% reduction in waste to landfill. The modeling approach is being extended to better represent the dynamics of industrial and ecological processes.