After rain events in densely populated areas, combined sewer overflows (CSOs) can have severe health-related effects upon surface water quality, as well as diffuse overland runoff and wastewater treatment plants (WWTPs). All of these sources emit pathogens and fecal indicator bacteria into the surface water, which the EU Bathing Water Directive addresses by giving threshold values for the indicators Escherichia coli and intestinal enterococci. This study presents a comparison between 21 scenarios of costs for processes that reduce the load of Escherichia coli and intestinal enterococci into the Ruhr River during and shortly after rain events. The methods examined include UV irradiation for WWTPs, integrated sewer management and treatment of CSOs with vertical flow constructed wetlands or performic acid. For pollution by diffuse overland flow, we evaluated organizational measures. The treatment of only diffuse pollution shows merely a slight effect on intestinal enterococci, but none on Escherichia coli and hence, was not considered further. Combining all three CSO reduction methods with the irradiation of WWTP effluent provides the best simulation results in terms of reducing both indicator bacteria.