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Karst hydrology is characterized by multiple springs, sinkholes, and losing streams resulting from acidic water percolating through limestone. These features provide direct connections between surface water and groundwater and increase the risk of groundwater, spring, and stream contamination. Anthropogenic activities (agriculture, tourism, urban and residential areas) accentuate the contamination potentials. The objectives of this article are to present a modification of the Soil and Water Assessment Tool (version 2005) that allows faster percolation through the soil substrate and recharge of the aquifer. This addition was necessary to simulate quick movement of water through vertical conduits that characterize karst topography. The model was calibrated for the James River basin, a large watershed (3,600 km2) in southwest Missouri. Losing streams were simulated by specifying high soil conductivities in the channels, and sinkholes were simulated as ponds with a high hydraulic conductivity at the bottom. Results indicated that the changes improved the partition of stream flow between surface and return flow. Water quality results indicated that the SWAT model can be used to simulate the frequency of occurrence of pollutant concentrations and daily loads. This case study highlights the possibilities and limitations in modeling flow and water pollutant movement in a karst watershed.