This study reports the toxicity and metabolism of methacrylonitrile (MeAN) in normal male Sprague-Dawley rats and those pre-treated with caffeine, alcohol or both. Rats were divided into groups often. One group received an oral dose by gavage of 6 % MeAN solution in corn oil (equivalent to 0.5 LD50). Other three groups of rats were pre-treated with alcohol (2 ml of 50% solution in water), caffeine (1 ml of 2% solution in water) or both alcohol and caffeine 12 hr before receiving MeAN dose by gavage. The rats were observed for mortality, cholinomimetic and central nervous system (CNS) effects and urinary dysfunction for 6 hr. The concentrations of cyanide, thiocyanate and glutathione (GSH) were determined in blood, liver, kidney and brain. Alcohol and alcohol + caffeine pre-treatment caused significant increase in cholinomimetic, CNS and urinary dysfunction effects of MeAN and mortality. However, caffeine alone pre-treatment protected rats from these effects. In the rats treated with MeAN alone and those pre-treated with alcohol and alcohol + caffeine the GSH concentrations significantly decreased in liver, brain and kidney. In the rats pre-treated with caffeine alone the concentrations of GSH were not significantly different from controls. In the rats treated with MeAN alone and those pretreated with alcohol and alcohol + caffeine the cyanide and thiocyanate concentrations increased in the blood and other organs up to 2-4 folds whereas in rats pre-treated with caffeine alone the concentrations of cyanide and thiocyanate were not significantly different from controls. Western Blot experiment showed CYP2E1 induction in rats pretreated with alcohol and MeAN. These results suggest that caffeine inhibited and alcohol enhanced toxicity and metabolism of MeAN.