The space–time–size distributions of seismicity during the last four decades (1973–2010) are used to identify megathrust asperities, the degree of plate coupling (hence potential future large earthquakes) and slab dehydration below the Andean margin (15°–48°S). This seismicity displays globally a typical magnitude distribution with a b value of 1.04 ± 0.024, for a magnitude of completeness of 4.5 and without considering aftershock sequences. However, this unitary b value of the entire catalogue masks large variations (0.6–1.7) in space and time, interpreted as related to different tectonics contexts or different states of the seismic cycle. The study has been performed for different regions (upper continental plate, upper and lower parts of the subducting oceanic plate) with respect to a 3-D slab geometry model all along the Andean margin. Low b values (0.6–0.8) are observed in areas that were ruptured by large Mw≥ 7.5 megathrust earthquakes. A temporal analysis of these features show that b values where low before these earthquakes and remain low after the relaxation of the aftershock phase, suggesting that they are related to time-persistent asperities within the seismogenic zone of the megathrust. Interestingly, a persistently low b value was observed from 2001 to the end 2009 within the southern limit of the Maule Mw= 8.8 earthquake, 2010 February 27. Our results also identify other low b asperities below the Chilean margin that have not ruptured during the last 40 yr and are places of potentially large megathrust earthquakes in the future. In contrast, large b values (1.1–1.7) are observed at seismicity clusters occurring inside the subducted slab beneath the Central Volcanic Zone (CVZ) of the Andes and below the forearc near the subduction point of aseismic ridges and fracture zones. Clusters below the CVZ are spatially related to relative large intermediate-depth earthquakes (like the Mw= 7.8 Tarapaca 2005 earthquake) and may reveal extensive thermally-driven dehydration of the oceanic lithosphere that favours wet mantle melting and therefore magmagenesis feeding the volcanic chain.