<p>The building stock in Europe accounts for almost half of primary energy use, highlighting the need for improved building performance. In the Mediterranean region, where cooling accounts for a significant share of energy consumption, passive strategies play a crucial role in reducing demand while maintaining comfort. Among these, the stack effect has been widely studied for multi-story systems, yet its potential application in staircases of two-story single-family houses, a common design typology in southern Europe, remains underexplored. This study investigates the potential of staircase design to enhance natural ventilation and reduce cooling demand, and evaluates which staircase and window-opening configurations are most effective. A whole-building energy modeling framework for a typical two-story single-family house in the Mediterranean region is developed, incorporating building geometry, construction materials and occupancy patterns, and accounting for coupled heat and mass transfer and interzonal airflows. Various staircase and window-opening scenarios are simulated to assess the stack effect impact on annual heating demand, cooling demand and operational costs for end-users. The results reveal that adding a staircase window in typical houses leads to an increase in energy savings from natural ventilation, ranging between 6–10% compared to relying solely on ground-floor windows. The influence of different building configurations, ventilation strategies, and orientations are examined. The findings provide a basis for architects and engineers to evaluate the feasibility of exploiting the stack effect, and to identify design strategies that maximize economic benefits from natural ventilation.</p>