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A simulation framework has been constructed for the Upper Mississippi River Basin (UMRB) using 131 subwatersheds that coincide with the boundaries of U.S. Geological Survey 8-digit Hydrologic Cataloging Unit watersheds. The framework integrates micro-level information on landuse from the Natural Resources Inventory (NRI), agricultural practices from Cropping Practice Survey (CPS), and the SWAT water quality model, together with a modeling interface denoted as i_SWAT. SWAT results are described for the Iowa River and Des Moines River watersheds, which are comprised of subsets of the 131 8-digit watersheds. Calibration and validation of the baseline was performed by comparing the SWAT output with the measured data. The SWAT model was found to simulate well on annual and monthly basis. Coefficient of determination (R2) values computed between the simulated and observed monthly stream flows and sediment yields for both the calibration and validation periods ranged from 0.65 to 0.83. Corresponding Nash-Sutcliffe model efficiency (E) statistics were between 0.46 and 0.83. Successful application of the SWAT model for the Iowa River and Des Moines River watersheds within the simulation framework provides a foundation for the next simulation phase, which entails simulating the entire UMRB for flow and associated water quality indicators.