During the investigational use of oral N-acetylcysteine as an antidote for poisoning with acetaminophen, 11,195 cases of suspected acetaminophen overdose were reported. We describe the outcomes of 2540 patients with acetaminophen ingestions treated with a loading dose of 140 mg of oral N-acetylcysteine per kilogram of body weight, followed four hours later by 70 mg per kilogram given every four hours for an additional 17 doses. Patients were categorized for analysis on the basis of initial plasma acetaminophen concentrations and the interval between ingestion and treatment. Hepatotoxicity developed in 6.1 percent of patients at probable risk when N-acetylcysteine was started within 10 hours of acetaminophen ingestion and in 26.4 percent of such patients when therapy was begun 10 to 24 hours after ingestion. Among patients at high risk who were treated 16 to 24 hours after an acetaminophen overdose, hepatotoxicity developed in 41 percent--a rate lower than that among historical controls. When given within eight hours of acetaminophen ingestion, N-acetylcysteine was protective regardless of the initial plasma acetaminophen concentration. There was no difference in outcome whether N-acetylcysteine was started zero to four or four to eight hours after ingestion, but efficacy decreased with further delay. There were 11 deaths among the 2540 patients (0.43 percent); in the nine fatal cases in which aminotransferase was measured before treatment, values were elevated before N-acetylcysteine was started. No deaths were clearly caused by acetaminophen among patients in whom N-acetylcysteine therapy was begun within 16 hours. We conclude that N-acetylcysteine treatment should be started within eight hours of an acetaminophen overdose, but that treatment is still indicated at least as late as 24 hours after ingestion. On the basis of available data, the 72-hour regimen of oral N-acetylcysteine is as effective as the 20-hour intravenous regimen described previously, and it may be superior when treatment is delayed.