ABSTRACT: While it is certain that some emergency department patients with acute drug overdose suffer adverse cardiovascular events (ACVE), predicting ACVE is difficult. The prognostic utility of the ECG for heterogeneous drug overdose patients remains to be proven. This study was undertaken to validate previously derived features of the initial ECG associated with ACVE in this population.We performed a prospective validation cohort study to evaluate adult emergency department patients with acute drug overdose at 2 urban university hospitals over 5 years in whom an emergency department admission ECG was performed. Exclusion criteria were alternate diagnoses, anaphylaxis, chronic drug toxicity, and missing outcome data. ACVE was defined as any of the following: circulatory shock, myocardial injury, ventricular dysrhythmia, or cardiac arrest. Blinded cardiologists interpreted ECGs for previously derived predictors of ACVE (ectopy, QT prolongation, nonsinus rhythm, ischemia/infarction), QT dispersion, and prominent R wave in lead AVR. Of 589 patients who met inclusion criteria (48% male, mean age 42), there were 95 ACVEs (39 shock, 64 myocardial injury, 26 dysrhythmia, 16 cardiac arrest). The most common drug exposures were as follows: benzodiazepines, opioids, and acetaminophen. Previously derived criteria were highly predictive of ACVE, with QT correction >500 ms as the highest risk feature (OR 11.2, CI 4.6-27).This study confirms that early ECG evaluation is essential to assess the cardiovascular prognosis and medical clearance of emergency department patients with acute drug overdose. Furthermore, this study validates previously derived high-risk features of the admission ECG to risk stratify for ACVE in this patient population.