We estimated the crustal thickness along an east-west transect across the Andes at lat 20°S and along a north-south transect along the eastern edge of the Altiplano from data recorded on two arrays of portable broadband seismic stations (BANJO and SEDA). Waveforms of deep regional events in the downgoing Nazca slab and teleseismic earthquakes were processed to isolate the P-to-S converted phases from the Moho in order to compute the crustal thickness. We found crustal-thickness variations of nearly 40 km across the Andes. Maximum crustal thicknesses of 70–74 km under the Western Cordillera and the Eastern Cordillera thin to 32–38 km 200 km east of the Andes in the Chaco Plain. The central Altiplano at 20°S has crustal thicknesses of 60 to 65 km. The crust also appears to thicken from north (16°S, 55–60 km) to south (20°S, 70–74 km) along the Eastern Cordillera. The Subandean zone crust has intermediate thicknesses of 43 to 47 km. Crustal-thickness predictions for the Andes based on Airy-type isostatic behavior show remarkable overall correlation with observed crustal thickness in the regions of high elevation. In contrast, at the boundary between the Eastern Cordillera and the Subandean zone and in the Chaco Plain, the crust is thinner than predicted, suggesting that the crust in these regions is supported in part by the flexural rigidity of a strong lithosphere. With additional constraints, we conclude that the observation of Airy-type isostasy is consistent with thickening associated with compressional shortening of a weak lithosphere squeezed between the stronger lithosphere of the subducting Nazca plate and the cratonic lithosphere of the Brazilian craton.