Avian vacuolar myelinopathy (AVM) is a neurologic disease of unknown etiology that affects bald eagles (Haliaeetus leucocephalus), American coots (Fulica americana), and several species of waterfowl. An unidentified neurotoxin is suspected as the cause of AVM, which has been documented at several reservoirs in the southeastern United States. We conducted diagnostic and epidemiologic studies annually during October–March from 1998–2004 at Clarks Hill/Strom Thurmond Lake on the Georgia/South Carolina border to better understand the disease. Avian vacuolar myelinopathy was confirmed or suspected as the cause of morbidity and mortality of 28 bald eagles, 16 Canada geese (Branta canadensis), six American coots, two great-horned owls (Bubo virginianus), and one killdeer (Charadrius vociferus). Active surveillance during the outbreaks yielded annual average prevalence of vacuolar lesions in 17–94% of coots, but not in 10 beavers (Castor canadensis), four raccoons (Procyon lotor), and one gray fox (Urocyon cinereoargenteus) collected for the study. Brain lesions were not apparent in 30 Canada geese collected and examined in June 2002. The outbreaks at this location from 1998–2004 represent the most significant AVM-related bald eagle mortality since the Arkansas epornitics of 1994–95 and 1996–97, as well as the first confirmation of the disease in members of Strigiformes and Charadriiformes.