Following availability in the United States in 2011, intravenous acetaminophen (IV APAP) was added to many hospital formularies for multimodal pain control. In 2014, the price of IV APAP increased from $12/g to $33/g and became a top 10 medication expenditure at our institution. To promote appropriate IV APAP prescribing and reduce costs. Quality improvement project at a 562-bed academic medical center involving all inpatient admissions from 2010 to 2017. Using Plan-Do-Study-Act (PDSA) methodology, our Pharmacy & Therapeutics (P&T) committee aimed to reduce inappropriate use of IV APAP by refinement of restriction criteria, development of clinical decision support in the electronic medical record, education of clinical staff on appropriate use, and empowerment of hospital pharmacists to enforce restrictions. Monthly IV APAP utilization and spending were assessed using statistical process control charts. Balancing measures included monthly usage of IV opioid, IV ketorolac, and oral ibuprofen. Five PDSA cycles were conducted during the study period. Monthly spending on IV APAP decreased from the highest average of $56 038 per month to $5822 per month at study conclusion. Interventions resulted in an 80% annual cost savings, or an approximate savings of $600 000 per year. Usage of IV opioids, IV ketorolac, and oral ibuprofen showed no major changes during the study period. IV APAP can be restricted in a safe and cost effective manner without concomitant increase in IV opioid use.