Avian vacuolar myelinopathy (AVM), a disease of unknown etiology, was first diagnosed in 1994 (Thomas et al. 1998) as the cause of morbidity and death of American coots (Fulica americana) and bald eagles (Haliaeetus leucocephalus) in the southeastern United States. The disease, now confirmed on 10 lakes in four southeastern states, also has been found in mallards (Anas platyrhynchos), ring-necked ducks (Aythya collaris), bufflehead (Bucephala albeola),one great horned owl (Bubo virginianus), and a killdeer (Charadrius vociferous). Histological examination of the central nervous system (CNS) shows a striking diffuse, spongy degeneration of the white matter, especially in the optic tectum and cerebellum. However, assessments of epidemiology, histopathology, and environmental chemistry/toxicology have failed to determine the cause. We investigated climatic variables in relation to occurrence and duration of the disease, changes in blood chemistry of affected birds, and potential sources of exposure. The disease occurred in sentinel mallards released on Lake Surf, North Carolina, in November, but not those released on the lake in late July or early January. A decrease in water temperature and turbidity and an increase in water pH were evident during the time when the disease was evident. Serum chemistry from AVM-affected sentinel mallards and wild coots did not indicate any particular organ system dysfunction. Food habit studies suggest that mallards and coots fed primarily on Hydrilla verticillata. A variety of cyanobacterial algal species also were found in two water samples collected in December 2000, including several species known to produce toxins. We concluded that algal species provide the most likely explanation for the cyclic, ephemeral nature of the AVM disease agent, but diagnosis of algal toxicosis is difficult.