Abstract The geochemical properties of the South-Eastern Alps volcanics (SEAV, Eocene age) call for a within-plate origin of the most primitive basalts, in contrast to the widespread calc-alkaline magmatism which developed some million years later northwestwards along the Periadriatic Lineament. The two contrasting magmatic suites that coexist in the Alpine area define binary mixing relationships in the Sr–Nd and Sr–Pb isotopic space, the end members of which being a crustal component (e.g. lower continental crust) and a HIMU-DMM component (e.g. the SEAV). The occurrence of a HIMU (high μ = high 238 U/ 204 Pb) component, which normally traces mantle plumes of deep mantle origin, in a tectonic regime dominated by collision tectonics (the tertiary convergence of European and Adriatic plates) can be explained by slab detachment and ensuing upwelling of mantle material through the lithospheric gap. We combine geochemical data and geophysical modelling to unravel the evolution of the Alpine slab after interaction with plume material and the genesis of the Alpine magmatism. The combination of changes in negative buoyancy caused by continental subduction and softening of a part of the slab caused by slab–plume interaction may act as a regulator for the time of slab breakoff and, consequently, for the variations of magmatism in the overriding lithosphere above a subduction zone. The thermal evolution of a subducting slab is modified by contact with the plume material which decreases significantly the total strength of the slab and favours slab detachment. Interactions between the HIMU component and the shallower depleted mantle can account for the geochemical characteristics of the SEAV. Counterflows of plume material towards the top of the subducting slab may also increase heating and partial melting of the overriding mantle wedge, giving rise to the calc-alkaline suite outcropping in the proximity of the Periadriatic Lineament.