OBJECTIVES: The relationship between acute high dose acetaminophen and hepatotoxicity is well established, however little is known about the relationships with chronic acetaminophen ingestion.  This study sought to determine the associations between acute and chronic prescription acquired acetaminophen use and hepatotoxicity.  METHODS: This was a retrospective case control study of a 10% random sample of the Pharmetrics LifeLink commercial claims data from 1997-2009.  Subjects had to be continuously enrolled and be >= 18 years of age.  Cases had to have at least one incident claim with a primary diagnosis of acute liver necrosis, hepatitis, hepatic coma, hepatorenal syndrome, or coagulopathy.  3:1 controls matched on age, gender, and geographic region were randomly chosen.  Acetaminophen maximum and average daily doses were calculated in a range of acute periods (7, 20, and 30 days) and in the chronic one year prior period.  Conditional logistic regression was used to estimate the risk of acetaminophen exposure adjusted for comorbidities, other hepatotoxic drugs, and health system factors. RESULTS: There were 1350 cases and 4050 controls with a mean age of 47.29 years and 53.85% were male.  116 (8.59%) cases and 144 (3.56%) controls were exposed to acetaminophen in the 30-day prior period with mean maximum daily doses of 3234.32 and 3021.40 mgs.   Hepatotoxicity was associated with any acute acetaminophen exposure that decreased with longer look back periods; 7 days (OR=2.23, p<0.001), 30 days (OR=1.84, p<0.001).  Cumulative dose in the year prior was not associated with hepatotoxicity (OR=1.05, p=0.889). Acute maximum daily doses >4gms/day were associated with greater risks of hepatotoxicity (OR=2.45, p<0.001). CONCLUSIONS: Acute exposure to prescription acquired acetaminophen is associated with increased risk of hepatotoxicity, however use over longer chronic periods was not.   Further research is necessary before the safety of chronic acetaminophen can be established.