BACKGROUND AND OBJECTIVES: Propofol facilitates deep sedation without requiring intubation and is often used by infusion to maintain sedation. Variability in ordering and preparation strategies resulted in significant propofol volumes wasted at the conclusion of procedures in our clinic. With drug shortages now common, we designed a quality improvement initiative to reduce our propofol waste. METHODS: Data collection during the preintervention phase reflected current practice trends. Two propofol dosing tables (≥50 or <50 kg) were designed to estimate the volume of propofol infusion required for sedations spanning 15 to 180 minutes. Nurses prepared propofol infusions as directed by these tables. The primary outcome measure was reduction in waste when the infusion was prepared by standardized strategy versus usual practice. Balancing measures included occurrences of insufficient infusion volume and premature awakenings from deep sedation. Waste volumes were plotted and displayed chronologically in statistical process control charts for the clinic and individual providers. RESULTS: A total of 155 patients received a propofol infusion to maintain deep sedation. The preintervention phase included 77 patients, and the intervention phase included 78 patients. Special cause variation was achieved in the intervention phase. Median (interquartile range) propofol waste volume per procedure declined from 45.6 mL (24.3–71 mL) to 14.3 mL (9.6–19.4 mL), representing a 68% waste reduction. CONCLUSIONS: Using an internally derived systematic approach to ordering and preparing a propofol infusion, we reduced variability, reduced propofol waste, and created cost savings for our organization. This approach is tailorable to other infusions and clinical settings.