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In the last century, large watersheds in Southern Europe have been impacted by a combination of anthropogenic and climatic pressures, which have rapidly evolved to change the ecological status of freshwater and coastal systems. A comparative analysis was performed for Ebro, Rhone, Po and Danube rivers, to investigate if they exhibited differential dynamics in hydrology and water quality that can be linked to specific human and natural forces acting at sub-continental scales. Flow regime series were analyzed from daily to multi-decadal scales, considering frequency distributions, trends (Mann-Kendall and Sen tests) and discontinuities (SRSD Method). River loads of suspended matter, nutrients and organic matter and the eutrophication potential of river nutrients were estimated to assess the impact of river loads on adjacent coastal areas. The decline of freshwater resources largely impacted the Ebro watershed on annual (-0.139 km(3) yr(-1)) and seasonal (-0.4% yr(-1)) scales. In the other rivers, only spring-summer showed significant decreases of the runoff coupled to an exacerbated flow variability (0.1-0.3% yr(-1)), which suggested the presence of an enhanced regional climatic instability. Discontinuities in annual runoff series (every 20-30 years) indicated a similar long-term evolution of Rhone and Po rivers, differently from Ebro and Danube. Higher nutrient concentrations in the Ebro and Po (+50%) compared to Rhone and Danube and distinct stoichiometric nutrient ratios may exert specific impacts on the growth of plankton biomass in coastal areas. The overall decline of inorganic phosphorus in the Rhone and Po (since the 1980s) and the Ebro and Danube (since the 1990s) mitigated the eutrophication in coastal ecosystems inducing, however, a phase in which the role of organic phosphorus loads (Po > Danube > Rhone > Ebro) on coastal productivity could be more relevant. Overall, the study showed that the largest South European watersheds are differently impacted by anthropogenic and climatic forces and that this will influence their vulnerability to future changes of flow regime and water quality.