Sheep received a single intragastric dose of 0.5, 1.0, 1.5, or 2.0 mmol F–/kg. Mild signs occurred at 1.5 mmol F–/kg and the animals recovered 2 days later. With the 2.0 mmol F–/kg dose all animals showed dullness, anorexia, and mild diarrhea which decreased from the third day. Dose-related congestion of duodenum, liver, kidney, and lung was observed in all animals. For the two higher doses kidney degeneration and tubular necrosis were associated with glomerular inflammation. Serum fluoride had a dose-related increase and was still significantly elevated on Day 7 for sheep given doses higher than or equal to 1.0 mmol F–/kg. Serum calcium and glucose levels were significantly lowered for all doses on the first day and the decrease was dose-related. In sheep given 2.0 mmol F–/kg total proteins and sodium were significantly lowered, whereas potassium and urea were increased (p < 0.05); alkaline phosphatase (ALP) and lactic dehydrogenase (LDH) were both lowered (p < 0.01) on the first day and ALP was still lowered on Day 7. For the highest dose glutamate dehydrogenase (GDH) was increased on Days 1 and 7 and gamma-glutamyl transferase (GGT) was increased on Day 1 and lowered on Day 7. Diuresis was increased for the two higher doses in Day 3 or 4 following dosage. A dose-related increase of daily fluoride excretion occurred for all doses on Day 1 and fluoride excretion was still significantly elevated on Day 7 except for the lowest dose. Daily urine GGT excretion was increased on the first day for all doses higher than or equal to 1.0 mmol F–/kg; GDH and LDH showed similar variations but less significant for LDH. On Day 7, SDH, GDH, ALP, and GGT in liver, GGT and LDH in kidney, and LDH in muscle were all lowered for the two higher doses. These data demonstrate that acute fluoride poisoning in sheep induces severe disturbances of kidney and liver function as reflected by altered activity of many enzymes.