The Cape Fear River is the largest and most industrialized riverine system in the state of North Carolina, USA. Long-term monitoring programs had never detected visible cyanobacterial blooms in this often-turbid river until 2009, when massive surface blooms of toxin-producing Microcystis aeruginosa occurred each summer through 2012. This river is the drinking water source for thousands of southeastern North Carolina residents, with the blooms centered near the major water intakes. The unprecedented blooms led to drinking water contamination by microcystins, potent hepatotoxins, and forced costly improvements to water treatment plants. We used multiple approaches to test hypotheses about sources and drivers of these unusual M. aeruginosa blooms. Analyses of flow, turbidity, temperature, nutrient, and phytoplankton biomass data did not reveal a plausible reservoir or lake source upstream of the impacted reaches nor any significant temporal changes in the river's propensity to support such blooms, nor were changes in the river's characteristics identified to explain bloom cessation after 2012. We used satellite imagery, targeted sampling, and molecular analyses to identify a likely source of Microcystis inoculum as a large, highly eutrophic waste lagoon with a discharge just above the bloom-impacted reach of the river. Subsequent improvements in that waste treatment facility led to a 50% decrease in nutrients and significant increases in nitro-gen (N) and phosphorus (P) ratios in the outfall, and subsequent cessation of the Microcystis blooms. The results suggest the possibility that similar situations may occur elsewhere, in which eutrophic waste treatment lagoons incubate and export harmful cyanobacterial blooms to seed adjacent river ecosystems