The first major epizootic of duck plague in free-flying waterfowl occurred at Lake Andes, South Dakota, in January and February, 1973. Duck plague was diagnosed in black ducks, mallards, pintail-mallard hybrids, redheads, common mergansers, common golden eyes, canvasbacks, American widgeon, wood ducks, and Canada geese, indicating the general susceptibility of ducks to duck plague. Clinical signs observed in mallards were droopiness, polydipsia, lethargy, reduced wariness, weakness, reluctance to fly, swimming in circles, bloody diarrhea, bloody fluid draining from the nares and bill, and terminal convulsions.Because the mallard was the most numerous and heavily infected species during the Lake Andes epizootic, gross and microscopic lesions of the gastrointestinal tract, liver, spleen, thymus, bursa of Fabricius, heart, lung, bone marrow, pancreas, and ovaries were described. Lesions of the esophagus and cloaca were in the stratified submucosal glands. In the small and large intestine, lesions were located in lymphocytic aggregates, lamina propria, and crypt epithelium. Hemorrhages and necrosis of hepatocytes and bile duct epithelium were noted in the liver. Diffuse necrosis of lymphocytic and reticuloendothelial tissue were evident in the spleen, bursa of Fabricius, and thymus. Hemorrhages in other tissues such as the lung and heart were often associated with lymphoid nodules, while those in organs such as the pancreas were associated with acinar necrosis. Intranuclear inclusion bodies were seen in stratified squamous epithelium of the esophagus and cloaca, crypt epithelium of the intestine, hepatocytes, bile duct epithelium, cells of Hassel's corpuscles, splenic periarteriolar reticular cells, and epithelial cells in the bursa of Fabricius.