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Paleoclimate reconstructions reveal that Earth system has experienced sub-millennial scale climate changes over the past two millennia in response to internal/external forcing. Although sub-millennial hydroclimate fluctuations have been detected in the central Andes during this interval, the timing, magnitude, extent and direction of change of these events remain poorly defined. Here, we present a reconstruction of hydroclimate variations on the Pacific slope of the central Andes based on exceptionally well-preserved plant macrofossils and associated archaeological remains from a hyperarid drainage (Quebrada Maní, ∼21° S, 1000 m a.s.l.) in the Atacama Desert. During the late Holocene, riparian ecosystems and farming social groups flourished in the hyperarid Atacama core as surface water availability increased throughout this presently sterile landscape. Twenty-six radiocarbon dates indicate that these events occurred between 1050–680, 1615–1350 and 2500–2040 cal yr BP. Regional comparisons with rodent middens and other records suggest that these events were synchronous with pluvial stages detected at higher-elevations in the central Andes over the last 2500 yr. These hydroclimate changes also coincide with periods of pronounced SST gradients in the Tropical Pacific (La Niña-like mode), conditions that are conducive to significantly increased rainfall in the central Andean highlands and flood events in the low-elevation watersheds at inter-annual timescales. Our findings indicate that the positive anomalies in the hyperarid Atacama over the past 2500 yr represent a regional response of the central Andean climate system to …