BACKGROUND: Following national and regional recommendations, intravenous lipid emulsion (ILE) has become established in clinical practice as a treatment for acute local anesthetic (LA) toxicity, although evidence of efficacy is limited to animal studies and human case reports. A collaborative lipid emulsion workgroup was therefore established by the American Academy of Clinical Toxicology to review the evidence on the effect of ILE for LA toxicity. METHODS: We performed a systematic review of the literature published through 15 December 2014. Relevant articles were determined based on pre-defined inclusion and exclusion criteria. Pre-treatment experiments, pharmacokinetic studies not involving toxicity and studies that did not address antidotal use of ILE were excluded. RESULTS: We included 113 studies and reports. Of these, 76 were human and 38 animal studies. One publication included both a human case report and an animal study. Human studies included one randomized controlled crossover trial involving 16 healthy volunteers. The subclinical LA toxicity design did not show a difference in the effects of ILE versus saline. There was one case series and 73 case reports of ILE use in the context of toxicity (83 patients) including CNS depression or agitation (n = 45, 54%), seizures (n = 49, 59%), hypotension, hypertension, EKG changes, arrhythmias (n = 39, 47%), cardiac arrest (n = 18, 22%), cardiopulmonary resuscitation, and/or requirement for endotracheal intubation and/or mechanical ventilation (n = 35, 42%). There were 81 (98%) survivors including 63 (76%) with no reported sequelae from the LA poisoning or ILE, although the presence or absence of sequelae was not reported in 15 (18%) cases. Animal studies included 29 randomized controlled studies, three observational studies, five case series, and one case report; bupivacaine was used in 29 of these reports (76%). Of 14 controlled experiments in animals, eight showed improved survival or time to return of spontaneous circulation and five no benefit of ILE versus saline or non-ILE treatments. Combining ILE with epinephrine improved survival in five of the six controlled animal experiments that studied this intervention. The studies were heterogeneous in the formulations and doses of ILE used as well as the doses of LA. The body of the literature identified by this systematic review yielded only a very low quality of evidence. CONCLUSION: ILE appears to be effective for reversal of cardiovascular or neurological features in some cases of LA toxicity, but there is currently no convincing evidence showing that ILE is more effective than vasopressors or to indicate which treatment should be instituted as first line therapy in severe LA toxicity.