The paper presents a mechanical approach for the assessment of large-scale seismic fragility for recurrent masonry building typologies in historical centres. Especially in the context of regional-scale analysis, the poor level of information drives analysts to develop suitable approaches to characterize in a synthetic way the seismic behaviour of the existing masonry building stock. Hence, the proposed framework arises from a matching between historical centres macro-classes and recurrent masonry building typologies defined by exploiting multisources data integration in GIS environment (e.g., census data, topographic cartographies, and information provided by the CARTIS form application). After, sets of mechanical models, which are sufficiently representative of the most widespread typologies on the regional territory, can be realized accounting for structural and morpho-typological features variability, as evincible from the available georeferenced database. Subsequently, nonlinear static analysis is adopted as analysis method where, for each model, Capacity/Demand ratio can be estimated for increasing levels of Peak Ground Acceleration. The obtained results are then processed according to Multiple Stripe Analysis method to derive typological fragility curves, which can be properly associated to historical centre macro-classes, covered by certain percentage of masonry building typologies. The proposed procedure was applied to the case study of Puglia region, allowing to investigate large portions of the building stock characterizing historical centres, by managing few information and by providing a methodology easily extendible to different context of applications.