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Lago Posadas is located at the foot of the Southern Patagonian Andes, in southwestern Argentina, where the early Miocene Santa Cruz Formation (SCF) shows thick and laterally continuous exposures. This region has been scarcely explored for fossil vertebrates since the first efforts by J.B. Hatcher in 1898-99. In this contribution, we performed sedimentologic and paleontological studies in order to reconstruct depositional environments and the associated fossil vertebrate fauna. Sedimentologic data suggest that the sedimentary record begins with restricted marine-estuarine deposits grading upward to fluvial floodplains and fluvial channels. Extensive floodplains, occasionally interrupted by low-sinuosity, sand-dominated channels, show dominant reddish coloration, moderate to low paleosol development, abundant crevasse splay sandstones and lack of vegetal remains, suggesting deposition in a low gradient, oxygenated setting under elevated sedimentation rates. Vertical stratigraphic trends are subtle, suggesting little paleoenvironmental changes during deposition of the whole SCF in this region. Paleocurrent directions, sandstone composition and paleogeographic reconstructions all indicate that deposition of the SCF was strongly associated to the contemporaneous uplift of the Andes. Fossil vertebrates analyzed are the result of our collecting effort and revision of museum collections. The faunal assemblage includes 31 taxa: 28 mammals and three birds. Mammals belong to the main groups recorded in other areas of the SCF (metatherians, xenarthrans, notoungulates, litopterns, astrapotheres and rodents). The assemblage allows a Santacrucian Age sensu lato assignment for the fauna at Lago Posadas. Taxonomic revisions of several taxa are necessary to further adjust the biostratigraphic significance of this association. The combined record of arboreal, browser and frugivores, on one side, and grazer mammals and rheas, on the other, suggest the presence of both trees and open environments. Frugivores, among primary consumers, and the secondary consumers guild are under-represented due to sample and fossil remain size biases. The sedimentologic and paleontological record of the SCF in Lago Posadas suggests that the uplift of the Southern Patagonian Andes acted as a primary control on basin subsidence and sediment supply, providing a special signature for sub-andean localities. However, previously registered climatic changes are poorly recorded in this study.