Marsdenia megalantha is a rupicolous shrub with succulent roots from the semiarid region of Brazil that is known to cause fatal poisoning in livestock. We reported spontaneous cases of poisoning by M. megalantha roots in bovine, caprine, ovine, and equine species. The clinical and pathological findings of experimental administration of M. megalantha to sheep, goats, a calf and a pig are reported. Three goats, two sheep and a calf were dosed once orally with freshly chopped roots at dose of 25 g wet plant/kg bw; another sheep and a pig were dosed with 10 g wet plant/kg bw. Poisoning occurred in all of the animals except the three goats. Clinical signs of poisoning included tachycardia, opisthotonus, ruminal bloat, dyspnea, nystagmus, mydriasis, ataxia, and recumbence with paddling movements. Pathological evaluation showed segmental laminar neuronal necrosis and spongiosis in the telencephalic cortex and degeneration of Purkinje cells. The picrate paper procedure detected no cyanide in the plant roots, but the reaction used for nitrate detection gave a strongly positive response. In conclusion, M. megalantha is a poisonous plant that produces acute poisoning characterized mainly by nervous disturbances. Livestock producers should offer alternative food during the dry and early rainy seasons to avoid the poisoning by this plant.