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Clinical decision support (CDS) displayed in electronic health records has been found to reduce the incidence of medication errors and adverse drug events (ADE). Recent data suggested that medication-related CDS alerts were frequently over-ridden, often inappropriately. Patients in the intensive care unit (ICU) are at an increased risk of ADEs; however, limited data exist on the benefits of CDS in the ICU. This study aims to evaluate potential harm associated with medication-related CDS over-rides in the ICU.This was a prospective observational study of adults admitted to any of six ICUs between July 2016 and April 2017 at our institution. Patients with provider-overridden CDS for dose (orders for scheduled frequency and not pro re nata), drug allergy, drug–drug interaction, geriatric and renal alerts (contraindicated medications for renal function or renal dosing) were included. The primary outcome was the appropriateness of over-rides, which were evaluated by two independent reviewers. Secondary outcomes included incidence of ADEs following alert over-ride and risk of ADEs based on over-ride appropriateness.A total of 2448 over-ridden alerts from 712 unique patient encounters met inclusion criteria. The overall appropriateness rate for over-rides was 81.6% and varied by alert type. More ADEs (potential and definite) were identified following inappropriate over-rides compared with appropriate over-rides (16.5 vs 2.74 per 100 over-ridden alerts, Fisher’s exact test P<0.001). An adjusted logistic regression model showed that inappropriate over-rides were associated with an increased risk of ADEs (OR 6.14, 95% CI 4.63 to 7.71, P<0.001).Approximately four of five identified CDS over-rides were appropriately over-ridden, with the rate varying by alert type. However, inappropriate over-rides were six times as likely to be associated with potential and definite ADEs, compared with appropriate over-rides. Further efforts should be targeted at improving the positive predictive value of CDS such as by suppressing alerts that are appropriately over-ridden.