We use the “isotope-paleotopography” method to resolve the topographic evolution of the Southern Central Andes and adjacent foreland to the east, at the latitude of 35°S. Our analysis is based on δ2H measurements from hydrated volcanic glass from 107 samples collected from a 55 to 10 Ma stratigraphic section in the Malargüe basin, and from an additional 11 samples of Quaternary tuffs. The results are supported by an analysis of a large dataset of modern meteoric water samples (n=197), which are used to characterize the relationship between orographic lifting and precipitation isotopes in the modern. Our interpretations are guided by the Orographic Precipitation and Isotopes (OPI) programs, which provide a full simulation of the flow of moist air over a specified 3D topography and the resulting condensation and fall out of rain and snow, and the isotopic fractionation associated with these processes. The OPI model is fit, in a least-squares sense, to the modern isotope data, which provides a way to test for moisture sources and to calculate how precipitation isotopes would be influenced by variations in climate.There are three important conclusions from these data: 1) OPI modeling of modern water isotopes shows that precipitation at the Malargüe study area is derived solely from the moist northeasterly winds. The isotopic fractionation along this wind path occurs by lifting over the Córdoba and San Luis basement highs, and during the initial rise up the east side of the range. Westerly moist air is able to pass over the range, but downslope flow over the east side means that this source becomes strongly undersaturated, so precipitation from this source is suppressed in this area. 2) Our volcanic glass data indicate that the hydrogen isotopic composition of precipitation, δ2H, has been strongly depleted, by −50 to −90 per mil, since 55 Ma to present. The only way to produce this depletion is by upslope flow of moist winds and associated precipitation over the eastern side of the range. The amount of isotopic fractionation remains fairly constant and similar to modern for the interval from 55 to 15 Ma, which indicates that the topography to the east of Malargüe has been fairly steady during that time interval. 3) Our δ2H record indicates that between 15 and 10 Ma, the topography upwind of Malargüe decreased by about 50%, and then increased by the same amount between 10 and 0 Ma. This subsidence event coincides with the Paranense marine transgression, and is also predicted by numerical modeling of mantle flow and dynamic topography associated with subduction of the Nazca plate.