Given the huge number of chemicals released into the environment and existing time and budget constraints, there is a need to prioritize chemicals for risk assessment and monitoring in the context of the European Union Water Framework Directive (EU WFD). This study is the first to assess the risk of 500 organic substances based on observations in the four European river basins of the Elbe, Scheldt, Danube and Llobregat. A decision tree is introduced that first classifies chemicals into six categories depending on the information available, which allows water managers to focus on the next steps (e.g. derivation of Environmental Quality Standards (EQS), improvement of analytical methods, etc.). The priority within each category is then evaluated based on two indicators, the Frequency of Exceedance and the Extent of Exceedance of Predicted No-Effect Concentrations (PNECs). These two indictors are based on maximum environmental concentrations (MEC), rather than the commonly used statistically based averages (Predicted Effect Concentration, PEC), and compared to the lowest acute-based (PNEC(acute)) or chronic-based thresholds (PNEC(chronic)). For 56% of the compounds, PNECs were available from existing risk assessments, and the majority of these PNECs were derived from chronic toxicity data or simulated ecosystem studies (mesocosm) with rather low assessment factors. The limitations of this concept for risk assessment purposes are discussed. For the remainder, provisional PNECs (P-PNECs) were established from read-across models for acute toxicity to the standard test organisms Daphnia magna, Pimephales promelas and Selenastrum capricornutum. On the one hand, the prioritization revealed that about three-quarter of the 44 substances with MEC/PNEC ratios above ten were pesticides. On the other hand, based on the monitoring data used in this study, no risk with regard to the water phase could be found for eight of the 41 priority substances, indicating a first success of the implementation of the WFD in the investigated river basins.