Fossiliferous sediments at Gran Barranca span a remarkable range of ages from the middle Eocene through the early Miocene, including the paleoceanographically significant Eocene-Oligocene transition (EOT). These strata provide an unparalleled opportunity to examine terrestrial isotope systematics attending global climate change in the southern hemisphere, as well as possible effects of Andean orogenesis on regional climate. Fossil tooth enamel shows minimal changes in oxygen isotope composition throughout the sequence, including a close bracket to the EOT. Variances in δ18O and δ13C from tooth enamel in all time slices near the EOT are statically indistinguishable, further suggesting minimal changes to climate seasonality, e.g. mean annual range of temperature. The presence of a transcontinental waterway west of Gran Barranca apparently buffered temperatures and isotope compositions through at least the mid-Oligocene, making these fossils sensitive to changes in global climate, but not to regional factors such as Andean uplift. The absence of an isotopic shift across the EOT is consistent with a small decrease in temperature (2-3º C), implying small changes to sea-surface temperatures for the Southern Ocean at this latitude. At 28-20 Ma, enable δ18O values drop compared to predicted compositions, whereas preliminary δ18O values of bone at 20 Ma rise, suggesting lower temperatures. Possibly cooling was caused by changes to ocean circulation, such as strengthening of the Antarctic Circumpolar Current (ACC). If so, the most likely timing of cooling (between 30 and 28 Ma) may correspond with isotope events Oi2, Oi2a, and/or Oi2b. Alternatively the largest decrease to δ18O at ~29 Ma also correlates with expected regression of a seaway intervening between the Andes and Gran Barranca, perhaps permitting an Andean isotopic rainshadow to manifest itself eastward. If so, then the Andes likely reached quasi-modern elevations by then and maintained those elevations to the present. Consistently low δ18O at ~12 Ma at Cerro Guenguel (~100 km from Gran Barranca) and for modern sheep teeth near Gran Barranca are attributable to a combination of low temperatures and presence of an Andean rainshadow.