The Groundwater Protection Project at the US Department of Energy Hanford Site in Washington State is currently developing the means to assess the cumulative impact to human and ecological health and the regional economy and cultures from radioactive and chemical waste that will remain at the Hanford Site after the site closes. This integrated system is known as the System Assessment Capability (SAC). The SAC Risk/Impact Module discussed in the article uses media- and time-specific concentrations of contaminants estimated by the transport models of the integrated system to project potential impacts on the ecology of the Columbia River corridor, the health of persons who might live in or use the corridor or the upland Hanford environment, the local economy, and cultural resources. Preliminary Monte Carlo realizations from the SAC modeling system demonstrate the feasibility of large-scale uncertainty analysis of the complex relationships in the environmental transport of contaminants on the one hand and ecological, human, cultural, and economic risk on the other. Initial impact results show very small long-term risks for the 10 radionuclides and chemicals evaluated. The analysis also helps determine science priorities to reduce uncertainty and suggests what actions matter to reduce risks.