Climate change in the coming decades could intensify extreme events such as severe droughts. Combined with the possible increase of water demands, these changes exert a large pressure on the water systems. In order to confirm this assumption, a set of scenarios was proposed in this study to consider the combined impact of climate changes and the increase in water demand on the main multiple-use reservoirs of São Francisco River, Brazil. For this purpose, five CMIP6 climate models were used considering two greenhouse gas emissions scenarios: the SSP2-4.5 and SSP5-8.5. The naturalized and withdraw streamflows were estimated to the adopted reser-voirs considering all existing, new and projected demands. The conjunction of scenarios indicat-ed an increase in Potential Evapotranspiration, a possible significant reduction in water availa-bility, a growth in water demand mainly for irrigation and a substantial reduction in the perfor-mance of the evaluated reservoirs.