The paper focuses on the development of territorial-scale fragility curves for reinforced concrete churches of Naples (Italy), particularly those characterized by a cathedral portal layout. Among the structures surveyed according to consolidated large-scale approaches, a specific typological class of reinforced buildings were defined. Large open interior spaces and significant vertical irregularities affect this kind of building, so that seismic performance is certainly worth to be investigated. This is the context of the present paper, which deals with the derivation of typological fragility curves by means of a mechanical model. In particular, the exceeding probability of given damage states is computed as a function of seismic intensity measures, such as Peak Ground Acceleration (PGA). This objective is achieved by simulating the seismic response of the churches through simplified non-linear response’s simulation of the structures under lateral loads accounting for relevant uncertain parameters. Thus, the associated Probability Density Function (PDF) has been defined and the fragility functions computed. An assessment of the resulting fragility formulations has been made referring to real data provided by relevant institutions (i.e., INGV) like those available in the area with reference, for instance, to the Irpinia-Basilicata 1980 earthquake. Ground shaking data have been retrieved from available shaking maps, including those published during the recent seismic sequence associated with the bradyseism phenomenon in the Campi Flegrei area. Comparison between the theoretical probability of exceedance for given limit states and the actual field response of selected structure is presented, allowing for some remarks on the significance of the computed fragility functions.