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Poisoning is the second leading cause of injury-related fatality in the United States. An elevated serum lactate concentration identifies medical and surgical patients at risk for death; however, its utility in predicting death in drug overdose is controversial and unclear.We aimed to evaluate the prognostic utility of serum lactate concentration for fatality in emergency department (ED) patients with acute drug overdose.This was a case-control study at two urban university teaching hospitals affiliated with a regional poison control center. Data were obtained from electronic medical records, poison center data, and the office of the chief medical examiner. Controls were consecutive acute drug overdoses over a 1-year period surviving to hospital discharge. Cases were subjects over a 7-year period with fatality because of drug overdose. Serum lactate concentration was obtained from the initial blood draw in the ED and correlated with fatality.During the study period, 873 subjects were screened with 50 cases and 100 controls included. Drug exposures and baseline characteristics were similar between groups. Mean lactate concentration (mmol/L) was 9.88 ± 6.7 for cases and 2.76 ± 2.9 for controls (p0.001). The receiver operating characteristic area under the curve for prediction of fatality was 0.87 (95% CI: 0.81-0.94). The optimal lactate cutpoint was 3.0 mmol/L (84% sensitivity, 75% specificity), which conferred a 15.8-fold increase in odds of fatality (p0.001).In this derivation study, serum lactate concentration had excellent prognostic utility to predict drug-overdose fatality. Prospective validation in the ED evaluation of drug overdoses is warranted.