Three sequential hurricanes, Dennis, Floyd, and Irene, affected coastal North Carolina in September and October 1999. These hurricanes inundated the region with up to 1 m of rainfall, causing 50- to 500-year flooding in the watershed of the Pamlico Sound, the largest lagoonal estuary in the United States and a key West Atlantic fisheries nursery. We investigated the ecosystem-level impacts on and responses of the Sound to the floodwater discharge. Floodwaters displaced three-fourths of the volume of the Sound, depressed salinity by a similar amount, and delivered at least half of the typical annual nitrogen load to this nitrogen-sensitive ecosystem. Organic carbon concentrations in floodwaters entering Pamlico Sound via a major tributary (the Neuse River Estuary) were at least 2-fold higher than concentrations under prefloodwater conditions. A cascading set of physical, chemical, and ecological impacts followed, including strong vertical stratification, bottom water hypoxia, a sustained increase in algal biomass, displacement of many marine organisms, and a rise in fish disease. Because of the Sound's long residence time (???1 year), we hypothesize that the effects of the short-term nutrient enrichment could prove to be multiannual. A predicted increase in the frequency of hurricane activity over the next few decades may cause longer-term biogeochemical and trophic changes in this and other estuarine and coastal habitats.