The catchment of the River Thames, a principal river system in southern England, is densely populated and highly vulnerable to changes in climate, land use and population. In order to predict its vulnerability to climate change, the Integrated Catchments Model for Nitrogen (INCA-N) has been applied to the whole of the River Thames. The model was calibrated from 1999 to 2006, to simulate streamflow and nitrate (NO3-N) concentrations. Despite the highly variable land use and river flows within the catchment, INCA-N reproduced both the hydrological regime and NO3-N dynamics in the river. A sensitivity analysis was performed on measured flow and in-stream nitrogen transformation rates. It showed that simulated NO3-N concentrations were sensitive to denitrification rates and flow velocity. Measured parameter values were generally within the range of behavioural model simulations. Temperature and precipitation scenarios from the UK Climate Projections 2009 climate model outputs were used to project possible future flow and NO3-N concentration changes. Results showed generally drier hydrological conditions, increased river NO3-N concentration in winter and decreases in summer. An assessment of the planned new reservoir at Abingdon showed that, if managed appropriately, it may help offset the impact of climate change on riverine NO3-N concentrations and London's water supply.