The aim of this paper is to describe the first report of spontaneous poisoning by Prosopis juliflora in sheep. From flock of 500 sheep at risk, four adult male sheep were affected. One died spontaneously and three other were examined, euthanized and necropsied. Neurologic examination focused particularly on motor and sensory-cranial nerve function, complete blood counts, serum biochemistry and urinalysis were done. The evolution of the disease was chronic and to present signs of poisoning, sheep had to ingest a diet containing at least 80% of P. juliflora pods during 21 months. The biochemistry revealed a substantial increase in creatine phosphokinase levels. Clinical signs included drooling of saliva, dropped jaw, tongue protrusion and loss of food from the mouth. Gross and histological lesions were similar to those previously reported in cattle and goats. Sheep are more resistant to poisoning by P. juliflora considering that it took 21 months of pod consumption to show clinical signs. There is no specific treatment for P. juliflora poisoning in ruminants.