Acute iron intoxication is associated with depletion of reduced glutathione in hepatocytes and changes in the glutathione system enzymes. We hypothesized that treatment with N-acetylcysteine (NAC), a glutathione reducing agent and an antioxidant, would reduce mortality in acute iron intoxication. We used a rat model to test this hypothesis. Male rats were assigned to 4 groups. Group 1 received 400 mg/kg elemental iron by oral gavage, group 2 received the same dose of iron followed by NAC, group 3 received NAC only, whereas group 4 received distilled water. Iron and liver transaminases in the blood, and glutathione system enzymes in the liver and erythrocytes were measured. Mortality in group 2 was significantly higher after 2, 6, and 24 hours compared with group 1 (P < .001). No deaths were observed in groups 3 and 4. Serum iron levels were significantly higher in group 2 rats compared to group 1 rats (P < .001). Hepatic and erythrocyte glutathione system enzymes were significantly lower among rats in group 2 compared to rats in group 1. The administration of NAC probably increased the absorption of iron through the gastrointestinal tract, causing higher serum iron levels with significant hepatic damage. These results indicate that in a rat model of acute iron intoxication, orally administered NAC may increase mortality.