Data from the Tono Uranium Deposit of central Japan were used to develop an improved approach for simulating uranium migration and retardation, while taking into account both long-term environmental changes and uncertainties in data. Based upon extensive field and laboratory investigations, conceptual and numerical models for environmental perturbations, including uplift, subsidence and faulting, were constructed. Model development was based on a novel adaptation of a safety assessment methodology that previously has been applied to radioactive waste repositories. A ‘reference scenario’ was developed using a systems analysis approach. This scenario is a best estimate of how the geological system and the uranium deposit reached their present states and includes descriptions of all major environmental perturbations. Uranium is mobilized from the uppermost Toki granite under relatively oxidizing conditions, and is then transported by groundwater into overlying sedimentary rocks. There, reducing conditions promote uranium deposition. A specially designed numerical model simulated the main features of this scenario. Many simulations were performed to identify key uncertainties to which the timing of ore deposition and uranium distribution are sensitive. A key finding is that retardation of U by processes other than precipitation of discrete U minerals, most probably sorption on solid phases, contributes significantly to the stability of the ore deposit. Sorption could potentially be important for confining the U within the sedimentary rocks in spite of environmental changes such as exhumation and seismic pumping. The approach could be used elsewhere, to assess the safety of deep geological high-level radioactive waste (HLW) disposal. A related application would be at potential future waste disposal sites, to prioritize site characterization so that the most safety-relevant uncertainties are reduced. There are also possible applications in other fields, most notably to assess the implications of alternative ore genetic models.