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Urban source water protection planning requires the characterization of sources of contamination upstream of drinking water intakes. Elevated pathogen concentrations following Combined Sewer Overflows (CSOs) represent a threat to human health. Quantifying peak pathogen concentrations at the intakes of drinking water plants is a challenge due to the variability of CSO occurrences and uncertainties with regards to the fate and transport mechanisms from discharge points to source water supplies. Here, a two-dimensional deterministic hydrodynamic and water quality model is used to study the fluvial contaminant transport and the impacts of the upstream CSO discharges on the downstream concentrations of Escherichia coli in the raw water supply of two drinking water plants, located on a large river. CSO dynamic loading characteristics were considered for a variety of discharges. As a result of limited Cryptosporidium data, a probability distribution of the ratio of E. coli to Cryptosporidium based on historical data was used to estimate microbial risk from simulated CSO-induced E. coli concentrations. During optimal operational performance of the plants, the daily risk target was met (based on the mean concentration during the peak) for 80% to 90% of CSO events. For suboptimal performance of the plants, these values dropped to 40% to 55%. Mean annual microbial risk following CSO discharge events was more dependent on treatment performance rather than the number of CSO occurrences. The effect of CSO-associated short term risk on the mean annual risk is largely dependent on the treatment performance as well as representativeness of the baseline condition at the intakes, demonstrating the need for assessment of treatment efficacy. The results of this study will enable water utilities and managers with a tool to investigate the potential alternatives in reducing the microbial risk associated with CSOs. (C) 2019 Elsevier B.V. All rights reserved.