AbstractDespite the amount of research focussed on the Alpine orogen, different hypotheses still exist regarding varying spatial seismicity distribution patterns throughout the region. Previous measurement-constrained regional 3D models of lithospheric density distribution and thermal field facilitate the generation of a data-based rheological model of the region. In this study, we compute the long-term lithospheric strength and compare its spatial variation to observed seismicity patterns. We demonstrate how strength maxima within the crust (~ 1 GPa) and upper mantle (> 2 GPa) occur at temperatures characteristic of the onset of crystal plasticity in those rocks (crust: 200–400 °C; mantle: ~ 600 °C), with almost all seismicity occurring in these regions. Correlation in the northern and southern forelands between crustal and lithospheric strengths and seismicity show different patterns of event distribution, reflecting their different tectonic settings. Seismicity in the plate boundary setting of the southern foreland corresponds to the integrated lithospheric strength, occurring mainly in the weaker domains surrounding the strong Adriatic plate. In the intraplate setting of the northern foreland, seismicity correlates to modelled crustal strength, and it mainly occurs in the weaker and warmer crust beneath the Upper Rhine Graben. We, therefore, suggest that seismicity in the upper crust is linked to weak crustal domains, which are more prone to localise deformation promoting failure and, depending on the local properties of the fault, earthquakes at relatively lower levels of accumulated stress than their neighbouring stronger counterparts. Upper mantle seismicity at depths greater than modelled brittle conditions, can be either explained by embrittlement of the mantle due to grain-size sensitive deformation within domains of active or recent slab cooling, or by dissipative weakening mechanisms, such as thermal runaway from shear heating and/or dehydration reactions within an overly ductile mantle. Results generated in this study are available for open access use to further discussions on the region.