Sediment samples from 24 tributaries of the Po River (Italy) were screened for selected trace elements (Cd, Cu, Hg, Pb, and Zn) and extractable organic compounds; a proxy for contamination by organic microcontaminants. The toxicity of sediment extracts was evaluated using a battery of biotests (Dugesia gonocephala, Paracentrotus lividus, and Tamnocephalus platyurus). Contamination by trace elements (including very high Hg pollution – 4 to 16ppm total Hg – in one sub-basin) reached potentially harmful levels only in the sediments of four tributaries; while contamination by organic microcontaminants was present in most sub-basins. Sediments from most study sites did actually show signs of anthropogenic stress and were able to elicit a toxic response. A more detailed evaluation of sediment quality in the Po River tributaries seems to be urgently needed for developing the necessary remediation strategies. Research priorities should include more thorough testing of sediment toxicity, determination of metal background levels in the various sub-basins and a more detailed identification of the organic micropollutants of possible concern.