Earthquakes have a long history of causing catastrophic damage to communities, resulting in structural collapses, loss of life, and economic turmoil. To enable informed decision-making and reduce the impact of these events in earthquake-prone regions, seismic risk studies provide relevant information to support stakeholders in the implementation of effective risk-based policies. The present work addresses the seismic reliability of the pre-code masonry building stock in the Metropolitan Area of Lisbon, which is the region of Portugal that faces the highest seismic risk due to the coexistence of moderate to high seismic hazard and highest demographic-economic exposure. The adopted general framework combines several hazard studies developed for the region under investigation and a synthetic database of masonry buildings representative of the pre-code building stock in Lisbon. Through analytical–numerical probabilistic approaches, new second-order hazard solutions with structural dependency are derived for the mean annual frequency of limit-state exceedance, which can be integrated into national application documents for Eurocode 8. In light of these results, the reliability assessment of the building stock is conducted in several Local Administrative Units by means of an improved SAC/FEMA formulation. The study represents the first comprehensive investigation of its kind in this region, providing essential information to define appropriate target safety level for code calibration and support future risk studies.