This clinical policy focuses on critical issues concerning the management of patients presenting to the emergency department (ED) with acetaminophen overdose. The subcommittee reviewed the medical literature relevant to the questions posed. The critical questions are: 1. What are the indications for N-acetylcysteine (NAC) in the acetaminophen overdose patient with a known time of acute ingestion who can be risk stratified by the Rumack-Matthew nomogram? 2. What are the indications for NAC in the acetaminophen overdose patient who cannot be risk stratified by the Rumack-Matthew nomogram? Recommendations are provided on the basis of the strength of evidence of the literature. Level A recommendations represent patient management principles that reflect a high degree of clinical certainty; Level B recommendations represent patient management principles that reflect moderate clinical certainty; and Level C recommendations represent other patient management strategies that are based on preliminary, inconclusive, or conflicting evidence, or based on committee consensus. This guideline is intended for physicians working in EDs.