The Boconó fault system is a major NE-SW, right-lateral strike-slip tectonic feature whose trace extends northeastward for 500 km, from the Tachira depression at the Colombian-Venezuelan border (near the city of Cúcuta) to the town of Morón (located on the Caribbean coast of Venezuela), within the Venezuelan (or Mérida) Andes, and slightly oblique to its main axis. The Boconó fault is morphologically expressed by a continuous straight alignment of longitudinal valleys, linear depressions, pull-apart basins, fault scarps, trenches, sag-ponds, linear ridges and saddles that suggest that this major tectonic feature is active. Moreover, several destructive earthquakes (e.g., 1610, 1812, 1894, 1932 and 1950) affecting the Andean region have been usually attributed to it, without any geological confirmation. Therefore, exploratory trenching on this major fault, the only reliable means of corroborating seismotectonic associations, were carried out at two different sites: slightly north of La Grita and few kilometres north of Cordero (Fundo Mis Delirios); both villages being located between the cities of Mérida and San Cristobal, in the southern part of the Venezuelan Andes. Both trenches revealed that the Boconó fault system has been active during Holocene time. On the one hand, the La Grita trench has particularly demonstrated that: a) the 1610 and 1894 earthquakes occurred along the single trace of the Boconó fault in this region; b) the magnitude of those two earthquakes can be estimated between M = 7.1 and 7.3; c) their return period is about 300 yr; and d) the Holocene oblique-slip rate ranges between 4.3 and 6.1 mm/yr (5.2 ± 0.9 mm/yr) along this segment of the fault system. On the other hand, the Boconó fault at the Mis Delirios trench does not show any deformation associated with the 1610, 1894 or any other historical earthquakes. The complexity of the Boconó fault trace—three active strands have been mapped around the Mis Delrios trench—may account for the lack of such recent ruptures on the excavated strand. However, the occurrence of two to three previous Holocene earthquakes on this fault strand is recorded in the alluvial deposits dug at the trench site.