The current Tactical Combat Casualty Care (TCCC) Guidelines recommend parenteral promethazine as the single agent for the treatment of opioid-induced nausea and/or vomiting and give a secondary indication of "synergistic analgesic effect." Promethazine, however, has a well-documented history of undesired side effects relating to impairment and dysregulation of the central and autonomic nervous systems, such as sedation, extrapyramidal symptoms, dystonia, impairment of psychomotor function, neuroleptic malignant syndrome, and hypotension. These may be particularly worrisome in the combat casualty. Additionally, since 16 September 2009, there has been a US Food and Drug Administration (FDA) black box warning for the injectable form of promethazine, due to "the risk of serious tissue injury when this drug is administered incorrectly." Conversely, ondansetron, which is now available in generic form, has a well-established favorable safety profile and demonstrated efficacy in undifferentiated nausea and vomiting in the emergency department and prehospital settings. It has none of the central and autonomic nervous system side effects noted with promethazine and carries no FDA black box warning. Ondansetron is available in parenteral form and an orally disintegrating tablet, providing multiple safe and effective routes of administration. Despite the fact that it is an off-label use, ondansetron is being increasingly given for acute, undifferentiated nausea and vomiting and is presently being used in the field on combat casualties by some US and Allied Forces. Considering the risks involved with promethazine use, and the efficacy and safety of ondansetron and ondansetron's availability in a generic form, we recommend removing promethazine from the TCCC Guidelines and replacing it with ondansetron.