The impact of combined sewer overflows on the Seine River was studied for the scientific interest of understanding highly transient situations and for the management challenges they represent. Measurements were made in the Seine River downstream of a combined sewer overflow (CSO) to identify the relevant variables describing the evolution of water quality. The combined effects of various processes influencing oxygen depletion after a rain event were analysed given all the available data. A complete oxygen balance was established to rank the relative importance of the processes. The model ProSe used for these tasks was designed in the framework of a long term multidisciplinary research program devoted to the Seine River catchment. A comparison of the model we used with existing models was done. The conceptual model was especially adapted for this highly impacted urban ecosystem. Apart from usual processes considered in river ecological modelling, sedimentation and erosion of particles, a biologically active and mobile benthic boundary layer (BBL), exchange of particles and diffusion of solutes between this BBL and the water column, detailed descriptions of algal and bacteria physiology were taken into account. To explain the oxygen depletion in the river, the more relevant variables appear to be the quantity of bacteria brought by the overflow and the biodegradable dissolved organic carbon concentrations. Specific contribution to the evolution of water quality of the river of particles that are sedimenting, was investigated, including the micro organisms brought by the overflows. For this highly eutrophicated river, the influence of the reduction of photosynthesis activity due to cloud cover was quantified. The influence of the toxicity of the CSO on the phytoplanktonic photosynthesis was studied experimentally and taken into account in the model. The resulting effect is a delayed oxygen depletion inside the plume of polluted water.