The post-closure performance of a generic horizontal drillhole repository for the disposal of spent nuclear fuel (SNF) is quantitatively evaluated using a physics-based numerical model that accounts for coupled thermal-hydrological flow and radionuclide transport processes. The model incorporates most subcomponents of the repository system, from individual waste canisters to the geological far field. The main performance metric is the maximum annual dose to an individual drinking potentially contaminated water taken from a well located above the center of the repository. Safety is evaluated for a wide range of conditions and alternative system evolutions, using deterministic simulations, sensitivity analyses, and a sampling-based uncertainty propagation analysis. These analyses show that the estimated maximum annual dose is low (on the order of 10−4 mSv yr−1, which is 1000 times smaller than a typical dose standard), and that the conclusions drawn from this dose estimate remain valid even if considerable changes are made to key assumptions and property values. The depth of the repository and the attributes of its configuration provide the main safety function of isolation from the accessible environment. Long-term confinement of radionuclides in the waste matrix and slow, diffusion-dominated transport leading to long migration times allow for radioactive decay to occur within the repository system. These preliminary calculations suggest that SNF can be safely disposed in an appropriately sited and carefully constructed and sealed horizontal drillhole repository.