Lethal and abrupt hyperthermia can be produced in rats when a sublethal dose of 2,4-dinitrophenol (10 µg/g, ip) is administered during anesthesia with 2 per cent halothane in a chamber kept at 25 C, but not at 20 C. Dinitrophenol injection, after about an hour, triples the metabolic rate, increases the rectal temperature to above 44 C, and produces skeletal muscle rigor at the time of death. Muscle mitochondria from rats treated with dinitrophenol + halothane show uncoupled oxidative phosphorylation but no acceleration of respiration. Treatment with halothane or dinitrophenol separately does not produce lethal hyperthermia or uncoupling in skeletal muscle mitochondria. Liver mitochondria from lethally hyperthermic rats show normal oxidative phosphorylation. Pretreatment with L-thyroxine does not sensitize rats to halothane, nor do peripheral anti-thyroxine agents prevent or reverse the dinitrophenol + halothane syndrome; Mg++ salts do prevent the muscle rigor. Lethal fulminant hyperthermia can be produced in laboratory animals not chosen for genetic susceptibility by administering an uncoupling agent during halothane anesthesia.