Stable isotope records of precipitation δ 18 O (δ 18 O prec ) have been used as paleoclimate and paleoelevation archives of orogens. However, interpretation of these records is limited by knowledge of how δ 18 O prec responds to changes in global and regional climate during mountain-building events. In this study the infl uence of atmospheric CO 2 levels, the extent of the Antarctic ice sheet, changes in Andean surface elevation, and the presence of the South American inland seaway on climate and δ 18 O prec in South America are quantifi ed using the GENESIS v3 atmospheric general circulation model with isotope-tracking capabilities. Results are presented in the context of Cenozoic South American climate and δ 18 O prec changes. More specifi cally, we fi nd: (1) Precipitation rates in the Andes are sensitive to Andean surface elevation, the seaway and, to a lesser extent, CO 2 levels. Increasing Andean elevations and the presence of a seaway both cause large increases in precipitation, but in different parts of the Andes. The growth of the Antarctic ice sheet is found to have a small infl uence on South American precipitation. (2) The stable isotopic composition of precipitation is sensitive to all of the parameters investigated. An increase in δ 18 O prec of up to 8‰ is found in simulations with higher atmospheric CO 2 . In agreement with previous studies, δ 18 O prec decreases with increasing Andean elevation by an amount greater than that predicted by the modern adiabatic lapse rate. Furthermore, the presence of an inland seaway causes a decrease in δ 18 O prec of 1-8‰ in the northern and central Andes. The amount of depletion is dependent on the isotopic composition of the seaway. Simulations without the Antarctic ice sheet result in δ 18 O prec that is 0-3‰ lower than the modern. Finally, time-specifi c simulations for the Miocene and Eocene show that δ 18 O prec has decreased during the Cenozoic and that local geographical gradients of δ 18 O prec have increased, particularly in regions of high modern elevation. We demonstrate that in addition to Andean uplift and associated climate change, CO 2 levels and an inland seaway are likely to have infl uenced δ 18 O carb records from South America. Consideration of these global and paleogeographic changes is necessary when interpreting paleoclimate or paleoelevation from stable isotope records of δ 18 O prec .