The southern Tyrrhenian Sea margin is dominated by deformations whose kinematics are relatively poorly constrained, and different models have been proposed to account for its recent evolution. Analysis of new structural and space geodesy data, combined with available geophysical information, reveal a deformation field characterised by subhorizontal NW-SE directed shortening and SW-NE directed extension. The main recognised regional-scale structure comprises E-W trending fault zones, namely the Ustica-Eolie Line and the Mt. Kumeta-Alcantara Line, connected by the NW-SE trending Marettimo, Trapani, San Vito, Palermo, Gratteri-Mt. Mufara and Eolie faults. This fault network displays a remarkable dextral strike-slip character, and has the features of a strike-slip duplex, that we indicate as the Southern Tyrrhenian Strike-Slip Duplex (STSSD). Analysis of available geophysical data and regional considerations based on plate-tectonic reconstructions suggest that the STSSD is a primary feature of lithospheric-scale importance. Our strike-slip duplex model differs significantly from previously proposed passive margin interpretations for the Tyrrhenian Sea margin offshore northern Sicily. The results of this investigation show the effectiveness of an integrated, multidisciplinary approach in the study of active deformation margins.