Technical Abstract: Locoweed poisoning is common in livestock and has been reported in elk (Cervus elaphus nelsoni). There are anecdotal reports of poisonings in pronghorn antelope (Antilocapra americana), but it is unknown if mule deer (Odocoileius hemionus) are susceptible. In locoweed endemic areas in Wyoming and Colorado, deer and elk have also contracted a transmissible spongiform encephalopathy, chronic wasting disease (CWD). Though spongiform diseases and locoweed poisoning produce distinct histologic lesions, no comparative histologic studies documenting these differences are available. The purpose of this study was to induce and describe chronic locoweed poisoning in deer. Two groups of four mule deer were fed alfalfa pellets or alfalfa pellets containing 15% Oxytropis sericea formulated to obtain a swainsonine dose of 1.5 mg swainsonine/kg bw/day. Locoweed poisoned deer lost weight and developed a scruffy, dull coat. After 120 exposure days they developed reluctance to move and when they were forced to move, subtle intention tremors were apparent. On day 180 all deer were euthanized and necropsied. Poisoned deer had extensive neuronal swelling and cytoplasmic vacuolation typical of locoweed poisoning in other species. Neuronal vacuolation was severe in cerebellar Purkinje cells and there were fewer Purkinje cells with increased numbers of empty baskets. Axonal swelling and dystrophy was found in many white tracts but was most severe in the cerebellar peduncles and the gracilis and cuneate fasciculi. These lesions were distinct from those of CWD and both control and treated deer were negative immunohistochemically for protease resistant protein (PrP). These findings indicate that deer are susceptible to locoweed poisoning and they develop lesions similar to those seen in other species. These histologic changes are distinct from those of CWD in deer. However, as the principle clinical changes of locoweed poisoning are wasting and emaciation with minimal neurologic deficits, the clinical presentation of locoweed poisoning in deer are very similar to CWD. This suggests it will be difficult to clinically differentiate the diseases, but the diagnosis is easily made with histologic and immunohistochemical studies.