Stable isotope records of precipitation δ18O (δ18Oprec) have been used as paleoclimate and paleoelevation archives of orogens. However, interpretation of these records is limited by knowledge of how δ18Oprec responds to changes in global and regional climate during mountain-building events. In this study the influence of atmospheric CO2 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 δ18Oprec in South America are quantified using the GENESIS v3 atmospheric general circulation model with isotope-tracking capabilities. Results are presented in the context of Cenozoic South American climate and δ18Oprec changes. More specifically, we find: (1) Precipitation rates in the Andes are sensitive to Andean surface elevation, the seaway and, to a lesser extent, CO2 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 influence on South American precipitation. (2) The stable isotopic composition of precipitation is sensitive to all of the parameters investigated. An increase in δ18Oprec of up to 8‰ is found in simulations with higher atmospheric CO2. In agreement with previous studies, δ18Oprec 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 δ18Oprec 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 δ18Oprec that is 0–3‰ lower than the modern. Finally, time-specific simulations for the Miocene and Eocene show that δ18Oprec has decreased during the Cenozoic and that local geographical gradients of δ18Oprec have increased, particularly in regions of high modern elevation. We demonstrate that in addition to Andean uplift and associated climate change, CO2 levels and an inland seaway are likely to have influenced δ18Ocarb records from South America. Consideration of these global and paleogeographic changes is necessary when interpreting paleoclimate or paleoelevation from stable isotope records of δ18Oprec.