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Increasing groundwater and soil salinity is a threat to the land and water resources in arid regions. Global warming will likely increase salinity of dryland river systems. In order to characterize salt loading into the semi-arid portion of the Rio Grande in south New Mexico and west Texas, we sampled seasonally (2009-2011) the river, agricultural drains, and saline groundwater. In addition to major element chemistry, these samples were analyzed for sulfur and oxygen isotope compositions (delta S-34 and delta O-18) of dissolved SO4 and in some cases for nitrogen and oxygen isotope compositions (delta N-15 and delta O-18) of dissolved NO3. Uranium isotopes (U-234/U-238 activity ratio) were also measured for selected samples. The natural inflow of basinal brines/ground-water (d(34)S of + 8 to + 11 parts per thousand) in the semi-arid Rio Grande study area was minor in the investigated seasons and could not be detected by the delta S-34 mass balance. However, we did find localized increases of delta S-34 (+ 2 to + 5 parts per thousand) in the Rio Grande that were attributable to salt loads from the intersections of agricultural drains with the water table of a natural salt flat and associated evaporative brine (delta S-34 of + 12 parts per thousand) in the shallow subsurface. In the areas, with higher water use for land irrigation, the delta S-34 of the river and drain water was relatively consistent (from similar to 0 to + 2 parts per thousand) compared to the delta O-18 (from similar to+ 2 to + 6 parts per thousand). Most likely, this resulted from application of S-rich fertilizers (e.g., ammonium sulfates, elemental S, sulfuric acid) with low delta S-34 (-2 to + 4 parts per thousand) and high delta O-18 (+ 9 to + 16 parts per thousand). Additionally, we observed considerably lower delta O-18 (SO4) in the Rio Grande and agricultural drains (<7 parts per thousand) compared to geologic and anthropogenic SO4 sources (+ 9 to + 16 parts per thousand), which likely resulted from microbial recycling of SO4 in soil of the irrigated land related to assimilatory sulfate reduction. Shallow recharge to the Rio Grande was also inferred from the lower U-234/U-238 activity ratios (1.62 to 1.88) compared to deeper groundwater (2.54 to 2.64) and the distinctive delta N-15 and delta O-18 values of nitrates (+ 5 to + 25 parts per thousand and -5 to + 15 parts per thousand, respectively) typical for septic effluents that are undergoing denitrification. Agricultural practices during flood irrigation intensify evaporation of the Rio Grande surface water and considerably increase water salinity. This process is also important in the evolution of water chemistry toward a Na-SO4-Cl-rich composition and precipitation of secondary calcite in soil profiles. (C) 2015 Elsevier B.V. All rights reserved.