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Water temperature and discharge are fundamental to lotic ecosystem function, and both are strongly affected by climate. In large river catchments, however, climatic effects might be difficult to discern from background variability and other cumulative sources of anthropogenic change arising from local land and water management. Here, we use trend analysis and generalised linear modelling on the Loire, the longest river in France to test the hypotheses that i) long-term trends in discharge and river temperature have arisen from climate change and ii) climatic effects on water quality have not been overridden by local effects. Over 32years (1977–2008), discharge in the Middle Loire fell by about 100m³/s while water temperature increased by 1.2°C with greatest effects during the warm period (May–August). Although increasing air temperature explained 80% of variations in water temperature, basin-wide precipitation showed no long-term trend and accounted for only 18% of inter-annual fluctuations in flow. We suggest that trends in abstraction coupled with a potential increase in evapo-transpiration at the catchment scale could be responsible for the majority of the long-term discharge trend. Discharge and water temperature explained only 20% of long-term variations in major water quality variables (conductivity, dissolved oxygen, pH, suspended matter, biochemical oxygen demand, nitrate, phosphate and chlorophyll-a), with phosphate and chlorophyll declining contrary to expectations from global change probably as a consequence of improved wastewater treatment. These data partially support our first hypothesis in revealing how warming in the Loire has been consistent with recent atmospheric warming. However, local management has had larger effects on discharge and water quality in ways that could respectively exacerbate (abstraction) or ameliorate (reduced point-source pollution) warming effects. As one of the first case-studies of its kind, this multi-parametric study illustrates the potential for complex interactions between climate change and other environmental factors in large rivers.