This article highlights a highly controversial practice issue referred to as nurse-administered propofol sedation, which affects registered nurses as well as advanced practice nurses in many different practice settings across the United States. Amid varied advice from professional organizations and state licensing boards, a thorough and systematic review of the current evidence provides insight into the question of safety associated with the practice. The evidence examined includes position statements from professional organizations and state boards, information from the United States Food and Drug Administration and the Joint Commission on Accreditation of Healthcare Organizations, and published research since 1999. The body of evidence demonstrates diverse positions; however, the empirical evidence in the author's opinion unanimously supports nurse-administered propofol sedation as a safe practice in nonintubated adult patients. Under research conditions, participants had a low incidence of untoward events and were adequately rescued with no intubations required and no deaths reported.