This work deals with the characterization of the spatial and temporal variability of water exchange fluxes from/to the Brenta river streambed (Veneto, Italy), critically important to regional water resources management. The aquifer system is structurally quite complex. It evolves from a large undifferentiated aquifer near adjacent mountain ranges to a wellstructured multi-layer system made up of six well-defined confined aquifers which constitute the noteworthy subsurface reservoirs of the area. Both the undifferentiated and the multiaquifer systems are heavily exploited for urban, industrial and agricultural uses. A three-dimensional groundwater flow model of the multi-aquifer system of the Central Veneto has been set up within a 3,300-km(2) area. The model integrates a large amount of available geological, geophysical, climatic and hydrologic data, has been specifically developed to analyze the behavior of such large, complex and well-monitored sedimentary system and to aid sustainable large-scale water resources management. A hydrothermal model of the river and of the underlying aquifer was implemented to improve the estimation, obtained for the 3D flow model, of the water exchange between the Brenta river and its underlying aquifer systems. The contribution of streambed exchanges is quantified by comparing simulations of water flow and heat transport to observed temperature and levels in river and in groundwater.