OBJECTIVES: To estimate the clinical and economic impacts of eliminating OTC access to acetaminophen in strengths of 500 mg or higher. METHODS: We developed a model to assess the clinical and economic impacts of the change in access over a 5-year horizon, using inputs from literature, market research, and commercial claims. In an intervention scenario where OTC extra-strength (ES) acetaminophen is prohibited, a cohort is followed as some switch to prescription acetaminophen, some to regular strength OTC acetaminophen, and some to OTC NSAIDs.  The model estimates the policy’s impact on incidence and costs of unintentional acetaminophen-induced acute liver failure (ALF) and NSAID-induced upper gastrointestinal bleeds (UGIB), using the literature to estimate the probability of developing each condition. The cumulative numbers of ALF and UGIB events, related deaths, associated health care costs, and consumer out-of-pocket (OOP) spending were compared under the baseline and intervention scenarios. RESULTS: By restricting OTC sale of ES acetaminophen, the model predicted that new cases, deaths, and medical spending associated with ALF decrease by 41% over the five-year period. However, new cases of UGIB and associated deaths are estimated to increase substantially as a result of this change. In total, the new policy is estimated to result in 1,603 additional deaths and over $824 million in incremental healthcare costs. Also, among consumers who did not experience ALF or UGIB, the cumulative OOP costs for additional physician visits and medication copayments were an estimated 24.5% higher under the policy change compared to the baseline scenario.  CONCLUSIONS: Evaluating a policy that prohibits OTC ES acetaminophen should consider the clinical and economic impacts associated with adverse events, particularly UGIB among patients who switch to NSAIDs. The incremental morbidity, mortality, and healthcare costs incurred may outweigh the benefits of reducing the incidence of ALF by eliminating OTC access to ES acetaminophen.