Several catastrophic building collapses^1–5 occur because of the propagation of local-initial failures^6,7. Current design methods attempt to completely prevent collapse after initial failures by improving connectivity between building components. These measures ensure that the loads supported by the failed components are redistributed to the rest of the structural system^8,9. However, increased connectivity can contribute to collapsing elements pulling down parts of a building that would otherwise be unaffected¹⁰. This risk is particularly important when large initial failures occur, as tends to be the case in the most disastrous collapses⁶. Here we present an original design approach to arrest collapse propagation after major initial failures. When a collapse initiates, the approach ensures that specific elements fail before the failure of the most critical components for global stability. The structural system thus separates into different parts and isolates collapse when its propagation would otherwise be inevitable. The effectiveness of the approach is proved through unique experimental tests on a purposely built full-scale building. We also demonstrate that large initial failures would lead to total collapse of the test building if increased connectivity was implemented as recommended by present guidelines. Our proposed approach enables incorporating a last line of defence for more resilient buildings.