We present a multiscale model that simulates coupled thermal and hydrological behavior driven by radioactive decay heat from a potential nuclear waste repository at Yucca Mountain, Nevada. We use this model to evaluate repository performance for different designs with respect to major thermal design goals (e.g., keeping waste packages dry). A locally boiling or globally boiling design uses rock dry out to create dry (low relative humidity (RH)) conditions around waste packages for a long period of time. A subboiling design eliminates boiling in the host rock (possibly reducing uncertainty) but is less effective at maintaining dry conditions. The addition of backfill increases the duration of RH reduction significantly without added boiling in the host rock but at the cost of higher waste package temperatures. The interaction between engineering design variables and natural system factors that affect thermohydrologic behavior is highly nonlinear. As a consequence, designs that differ by seemingly small details can result in markedly different thermohydrologic behavior and consequently repository performance, whereas with regards to other details, large differences may have little or no effect.