<p>This study presents a comparative assessment of potential economic losses caused by seismic events in two high-risk Mediterranean urban centers: downtown Blida (Algeria) and the municipality of Orihuela (Spain). Both regions face serious seismic threats due to their proximity to active fault systems, dense populations, and aging building inventories that remain highly vulnerable to ground shaking. The main goal of this research is to bridge the gap in current risk assessments by estimating economic losses for Blida (Algeria) and the Mean Damage Ratio for Orihuela (Spain) using different approaches to accounting for local site effects and different ground motion prediction equations (GMPEs). Applying a scenario-based framework via the Seismic Loss Estimation using a Logic Tree Approach (SELENA) software, the study modeled four credible earthquake scenarios for Blida (M_W 6.5–7.1) and a simulated repetition of the historic 1829 Torrevieja earthquake (M_W 6.3–6.9) for Orihuela. The methodology employed a logic-tree approach to manage epistemic uncertainties, incorporating regionally validated Ground-Motion Prediction Equations (GMPEs) and the Euro-Mediterranean RISK-UE building taxonomy to classify thousands of residential and historical structures. The findings reveal critical vulnerabilities in both urban contexts. In Blida, near-fault scenarios (M_W 7.1) yield a global Mean Damage Ratio (MDR) of approximately 53%. They could cause the collapse of more than 75% of masonry buildings, resulting in peak economic losses of €32&#xa0;million in the most exposed districts. Conversely, reinforced concrete structures exhibited much higher resilience. In Orihuela, a recurrence of the Torrevieja event could severely damage the historical “Old Town,” where MDR exceeds 78%. The Orihuela case also highlights a typical characteristic of Mediterranean cities: the residential population tends to increase during summer due to tourism, so fatalities will also increase if the earthquake occurs during the summer rather than winter. Although a detailed human loss study was not the goal of this study, we can indicate that a 60% increase in the residential population will also be reflected in a large increase in the affected population. By analyzing these two distinct Mediterranean sites, the study demonstrates that integrating local soil amplification models with detailed building typologies is essential to accurately quantifying the severe financial exposure inherent in these historical urban centers. These results provide a vital evidence base for urban planners and policymakers to prioritize targeted retrofitting and develop more robust disaster mitigation strategies for vulnerable coastal and inland cities.</p>