Technical Abstract: Some species are more likely to develop both clinical and histologic locoism. Mice and deer are relatively resistant where sheep and cattle are more susceptible. Horses appear to be even more sensitive. The purpose of this study is to determine toxic locoweed doses and describe the progression of locoweed poisoning in horses. Sixteen mares were fed a mixed locoweed ration to obtain swainsonine doses of 0.0, 0.2, 0.6, and 1.8 mg swainsonine/kg body weight/day. After 90 days two mares from each group were necropsied and tissues were collected for chemical, histology and ultrastructural studies. The remaining 2 animals were allowed to recover for 45 days after which they were euthanized and necropsied. After 10 days of treatment the mares from the 0.6 and 1.8 mg groups were depressed, anorexic, hesitant to move and they had subtle intention tremors when moving. These signs became more severe and after 45 days, the 5/6 mares had cystic ovaries with abnormal estrus cycles. With 60 days of treatment the 0.2 mg/kg groups also became depressed and started to lose weight. At necropsy the treated animals were thin with lack of visceral and subcutaneous adipose tissue. Histologically the 0.6 and 1.8 mg swainsonine groups all had severe vacuolation of nearly all neuronal and visceral tissues. The 0.2 mg swainsonine group had mild vacuolation of the Purkinje cells and renal tubular cells. The mares that were allowed to recover began to have normal estrus cycles and near the end of the recovery period began to eat better and gain weight. Histologically these animals had some neuronal vacuolation with loss of neurons and axonal dystrophy (spheroids). These results indicate horses are much more sensitive to locoweed poisoning than other livestock species. They develop severe clinical signs quicker and they are slower to recover than other livestock species. Though previously poisoned mares recover reproductive function, they have permanent neurologic damage and are a risk if they are ridden or worked.