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Understanding regional climate variability is necessary in order to assess the impacts of climate change. Until recently, the best methods for evaluating regional climate variability were via observation networks and coarse-gridded reanalysis datasets. However, the recent development of high-resolution reanalysis datasets offers an opportunity to better evaluate the climatologically diverse continent of South America. This study compares NCEP’s CFS reanalysis dataset with NCEP’s coarser-resolution reanalysis II dataset to determine if CFS reanalysis improves our ability to represent the regional climate of South America. Our results show several regional differences between the CFSR and Re2 data, especially in areas of large topographical gradients. A comparison with the University of Delaware and TRMM precipitation datasets lends credence to some of these differences, such as heavier precipitation associated with anomalous 925 hPa westerlies over northwestern Peru and Ecuador during El Niño. However, our results also stress that caution is advised when using reanalysis data to assess regional climate variability, especially in areas of large topographical gradient such as the Andes. Our results establish a baseline to better study climate change, especially given the release of IPCC AR5 model simulations.