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With concerns about future catastrophic disasters, elevated CO2 concentration (eCO(2)), global warming and vegetation changes have received much attention globally. In recent years, studies have suggested controlling climate change should be based on regional impacts. However, regional quantitative assessments of respective and combination influences of CO2, temperature and vegetation variations on water resources remain limited. To address this issue, a comprehensive framework is developed. This framework integrates a dynamic vegetation simulation approach, a biosphere hydrological model and a variance-based sensitivity analysis approach which enables identification of predominant influential factors including their combinations. A medium-sized river basin in northeast China is used to illustrate the application based on different CO2 concentration and temperature rise assumptions. Validation using MODIS products shows the proposed approach can simulate Leaf Area Index (LAI) changes well. Results show sum of the influences of LAI and temperature variations on transpiration are more than 1.6 times higher than physiological effects of eCO(2) in growing seasons, which implies more water could be transpired than conserved with eCO(2), global warming and LAI changes. Results also show runoff increases with eCO(2) and decreases with increasing temperatures, but LAI changes play a dominate role in runoff decrease in hot summer. Therefore, considering LAI changes is of utmost importance in projections of future water resources, and severity of future water shortage could be underestimated if LAI changes are neglected. This research is useful in gaining insights into the complicated impacts of eCO(2), global warming and LAI changes on regional water security and sustainability.