Fission-track (FT) thermochronology has been applied to investigate the low-temperature cooling and denudation history of the Patagonian Andes along the southern part of the intra-arc transpressional Liquiñe-Ofqui fault zone between 42° and 46°S. The Liquiñe-Ofqui fault is shown to have been the focus of enhanced cooling and denudation initiated between ca. 16 and 10 Ma. Several fault blocks with different cooling histories are identified; these are separated by major oblique- or reverse-slip faults proposed to form the eastern part of a major (crustal-scale) dextral transpression zone. Local very fast rates of cooling and denudation between ca. 7 and 2 Ma were coeval with collision of the Chile Rise (an active mid-oceanic ridge) with the Peru-Chile Trench between ∼47° and 48°S. This location is close to the southern termination of the Liquiñe-Ofqui fault, implying that the collision of the ridge was a major force driving late Cenozoic transpression. The lack of significant cooling and denudation before ca. 16 Ma is indicative of pure strike-slip or transtensional movement along the Liquiñe-Ofqui fault before the collision of the ridge. Digital landscape analysis supports glacial and periglacial erosion as the main contributor to denudation since ca. 7 Ma, leading to restriction of topographic development. The combination of transpression-induced rock uplift and glacial erosion is shown to be very effective at causing localized denudation. Anomalously young FT ages along the Liquiñe-Ofqui fault are attributed to the existence of a late Cenozoic localized heat-flow anomaly along the fault.