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The role and extent of climate as a cause of the expansion and decline of human cultures is still debatable. It is clear, however, that human environment interactions are enhanced and interplay more closely in climatically sensitive areas such as around hydrologically closed basins. Lago Cardiel is located at 49 degrees S in the very arid rain shadow east of the Andes, providing an exceptionally receptive system to changes in hydrological balance. Results of a geophysical survey combined with sedimentological and geochemical studies provide a continuous Lateglacial-Holocene record of substantial water-level changes. These variations, combined with archaeological results from the catchment area, offer a unique possibility to explore the pattern of peopling within this remote area of the globe and its possible relation to climate change. Human occupation in Patagonia is well documented towards the Andes throughout the entire Holocene. Archaeological data from the Lago Cardiel basin, however, show an apparent lack of human activity during the first part of this period, which coincides with well-constrained high lake levels. Our results show an intriguing coincidence between low lake level and increasing human occupation, suggesting that the Lago Cardiel basin has focused human use during intervals with relatively lower effective moisture such as during the Late Pleistocene, but its evidence may have been submerged. This interpretation is confirmed by archaeological remains from Lago Strobel, another perennial lake with a comparable catchment located in the same climatic region and thus sharing the same climatic history as Lago Cardiel. Copyright (C) 2009 John Wiley & Sons, Ltd.