The Rhône watershed extends over almost one hundred thousands square kilometers, i.e. one fifth of the metropolitan French territory. The Rhône is the major River entering the Western Mediterranean Sea as it generates the main source of sediments and freshwater (50%) to the sea, with an average water discharge of 1700 m3 s-1. The River input affects primary production significantly in the north-western Mediterranean area and plays a leading role on the marine ecosystem functioning in the whole Gulf of Lion. Almost twenty nuclear reactors are situated along the Rhône valley, representing Europe’s biggest concentration of nuclear power plants. Down flow all these installations the spent fuel reprocessing plant of Marcoule released over many years most of the liquid radioactive wastes including plutonium isotopes in the Rhône river. Artificial radionuclides also originate from the weathering of the catchment basin labeled by both the global and the Chernobyl accident atmospheric fallout. These radioactive inputs have led to a permanent contamination of the Rhône river waters. Long-term chronological series of artificial radionuclide activities within the waters at the lower reaches of the Rhône river were acquired from 1979 to 2002. These data give evidence for various radioecological responses of the aquatic system over years. Based on these observations several major radioecological sensitivity factors for river waters are identified.