Sicily Channel is a portion of Mediterranean Sea, between Sicily (Southern Italy) and Tunisia, representing a part of the foreland Apennine-Maghrebian thrust belt. The seismicity of the region is commonly associated with the normal faulting related to the rifting process and volcanic activity of the region. However, certain seismic patterns suggest the existence of some mechanism coexisting with the rifting process. In this work, we present the results of a statistical analysis of the instrumental seismicity and a reliable relocalization of the events recorded in the last 30 yr in the Sicily Channel and western Sicily using the Double Difference method and 3-D Vp and Vs tomographic models. Our procedure allows us to discern the seismic regime of the Sicily sea from the Tyrrhenian one and to describe the main features of an active fault zone in the study area that could not be related to the rifting process. We report that most of the events are highly clustered in the region between 12.5◦–13.5◦E and 35.5◦–37◦N with hypocentral depth of 5–40 km, and reaching 70 km depth in the southernmost sector. The alignment of the seismic clusters, the distribution of volcanic and geothermal regions and the location of some large events occurred in the last century suggest the existence of a subvertical shear zone extending for least 250 km and oriented approximately NNE–SSW. The spatial distribution of the seismic moment suggests that this transfer fault zone is seismically discontinuous showing large seismic gaps in proximity of the Ferdinandea Island, and Graham and Nameless Bank.