Context: The intravenous (IV) N-acetylcysteine (NAC) regimen used worldwide in paracetamol overdose is complex with three separate weight-based doses and is associated with a high incidence of adverse events including non-allergic anaphylactoid reactions (NAARs). In 2012, Denmark adopted the two-bag IV NAC regimen which combined the first two infusions of the three-bag regimen and kept the third infusion unchanged. We compared the safety and efficacy of the two-bag IV NAC regimen with the traditional Danish three-bag regimen. Methods: A medical chart review was conducted in three Danish medical centers from January 2012 through December 2014. Safety and efficacy data were compared for patients who received the traditional infusion protocol in Denmark or the 20-h two-bag IV regimen. Results: Four hundred and ninety-three cases received the two-bag regimen and 274 received the three-bag regimen. The overall incidence of NAARs was 9% with all being mild to moderate in intensity. Fewer subjects in the two-bag group (4%) developed NAARs compared to 17% in the three-bag group (p <.001). Overall, 31 patients (4%) developed hepatotoxicity. There was no apparent difference in hepatotoxicity rates between the groups and no deaths or liver transplants. Patients receiving the two-bag regimen had fewer interruptions or delays (5%) compared to the three-bag regimen cohort (12%). Overall, there were very few medication errors reported (1%). Conclusions: The incidence of NAARs was lower in patients receiving acetylcysteine in a two-bag regimen compared to the traditional Danish three-bag regimen without an apparent reduction in efficacy.