The effect of griseofulvin treatment on signal grass (Brachlaria decumbens) toxicity was studied in 27 male Wiltshire Indigenous Malaysian crossbred sheep. Grazing on signal grass generally decreased the activity of the drug metabolizing enzymes in livers and kidneys. Griseofulvin oral administration of 5 mg/kg body weight for 5 consecutive days every other week for 10 w increased the hepatic concentration of cytochrome P-450 and the activity of phase II drug metabolizing enzymes (UDP-glucuronyltransferase and glutathione-S-transferase) while it decreased the hepatic and increased the renal activity of phase I enzymes aminopyrine-N-demethylase and aniline-4-hydroxylase. Griseofulvin did not protect sheep against B decumbens toxicity as 5/7 animals treated with griseofulvin and grazed on B decumbens showed signs of the plant toxicity.