This paper proposes a new seismogenic interpretation of mainland and central-southern Sicily, based on an integrated structural–kinematic–seismological approach. Through analysis of available structural and geophysical data, the tectonic setting, the major kinematic units and the crust geometry of the Sicilian southward-verging fold-and-thrust belt system are schematized in sections and in map form. The depth-contour lines of the outermost basal thrust plane, which dates back to Plio-Pleistocene times with some evidence of Holocene activity, are reconstructed. This plane, here named Sicilian Basal Thrust (SBT), emerges along the southward convex Sciacca–Gela–Catania front and reaches the base of the crust at a depth of about 30 km beneath northern Sicily. Additionally, an important regional upper crust splay, with the same arched shape, has been identified some kilometres northward. In order to detect any possible indication of seismogenic activity linked to ongoing deformation of the SBT and its splay, we analyzed the distribution and kinematics of the instrumental seismicity in the period between 1981 and 2006. Particular attention was given to the background seismicity (Ml up to 4.6) located beneath the sedimentary cover at Mt. Etna, as it allows individuating a northward deepening seismogenic volume undergoing an average N–S compression, which corresponds well with the SBT geometry in section view. A merged dataset of all the known major historical and instrumental events (moment magnitude ≥ 4.5) that occurred above the SBT 0-to-30 km depth-contour lines from 217 B.C. to 2006 was compiled and analyzed. Based on information from instrumental data and/or on speculations on the shape and extent of the historical earthquake macroseismic fields, two major ranges of hypocentral depths have been schematically identified within the merged dataset: an upper crust range (in average < ~ 10 km) and a mid-to-lower crust range. Focal mechanisms available in the literature show prevailing reverse and reverse-oblique kinematics, compatible with a nearly average N–S shortening and with some field evidence of active fold-and-thrust deformation at the SBT front and along its inner splay. Several moderate earthquakes (nearly 40 in the last 400 years with moment magnitude ranging from 4.5 to 5.5) and a few more energetic events with moment magnitude up to ~ 6.0, such as the Mineo 1624, the Belice 1968 and the Catania 1818 events, can be attributed to an ongoing activity of the SBT. In previous studies, these events had been often attributed to isolated N–S strike-slip sources located within the Hyblean-Pelagian foreland, while all the interposed areas had been considered aseismic, as well as the SBT had been considered inactive. The identification in the SBT of a unique regional-scale seismogenic structure capable to connect the active deformation and the seismic activity of the western, central and eastern areas of mainland Sicily and those of central-southern Sicily evidently has strong implications in terms of seismic hazard assessment. In fact, it allows the definition of a new homogeneous compressional seismotectonic province, which extends between the SBT surface front line and the surface projection of the 25 km SBT depth-contour line. A subdivision in two sub-provinces, a shallow one above the 0–10 km SBT segment and a deep one above the 10-to-25 km SBT segment, is also considered and the energy released of the associate earthquakes evaluated. To conclude, the proposed model is discussed in comparison with other models from the literature and some important open problems are put forwards.