Barbamarco Lagoon (area = 7 km2) is in the Po River Delta, adjoining the Northern Adriatic Sea, and supports a commercially valuable clam (Tapes philippinarum) fishery. This study investigated interactions of the lagoon with adjacent coastal waters and inland riverine inputs by modelling both the lagoon and the Northern Adriatic Sea, using a coupled three-dimensional (3D) hydrodynamic-ecological model (ELCOM-CAEDYM) adapted to include the clam population. The clam model accounted for carbon (C), nitrogen (N) and phosphorus (P) biomass in the benthos through parameterisations for filtration, excretion, egestion, respiration, mortality, and harvesting. Multiple clam size classes were included in a new population dynamics sub-model. Output from the coupled model was validated against hydrodynamic and water quality data from intensive field sampling and routine monitoring. Time scales of tidal flushing, primary production and clam grazing were investigated with the model to demonstrate that food supply to clam populations is dominated by phytoplankton inputs from the Northern Adriatic Sea. Effects of clam cultivation on nutrient concentrations and phytoplankton biomass in Barbamarco Lagoon were primarily localised, with strong tidal flushing minimising impacts of clam filtration on lagoon-wide nutrient concentrations at current clam stocking levels. Clam populations were found to alter the cycling of nutrients in the system, causing the lagoon to become a net sink for particulate organic matter and to export dissolved organic matter to the adjacent sea via tidal flushing. Ecosystem health and sensitivity of nutrient cycles to clam cultivation are important considerations for the long term sustainable management and potential expansion of the fishery.