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Streamflow in the Missouri River basin increased substantially during the 20th century, with multiple floods occurring since 1990 that were unprecedented in the instrumental record. Using an ensemble of land-surface model outputs and water budget simulations, we examined the extent to which increased flow was driven by interannual climate variability, anthropogenic climate trends, land-use and land-cover change (LULCC), and CO2 fertilization. Climate variability explained~ 75% of increased flow since mid-century, while anthropogenic warming had a net negative effect on flow, increasing evapotranspiration more than precipitation. Anthropogenic warming also led to seasonal redistribution of runoff generation in the upper basin from summer to spring, likely due to reduced snow accumulation and earlier snowmelt. LULCC and CO2 fertilization amplified climate-driven streamflow increases, leading to …