Abstract Objective To estimate the national cost of ADEs resulting from inappropriate medication-related alert overrides in the U.S. inpatient setting. Materials and Methods We used three different regression models (Basic, Model 1, Model 2) with model inputs taken from the medical literature. A random sample of 40 990 adult inpatients at the Brigham and Women’s Hospital (BWH) in Boston with a total of 1 639 294 medication orders was taken. We extrapolated BWH medication orders using 2014 National Inpatient Sample (NIS) data. Results Using three regression models, we estimated that 29.7 million adult inpatient discharges in 2014 resulted in between 1.02 billion and 1.07 billion medication orders, which in turn generated between 75.1 million and 78.8 million medication alerts, respectively. Taking the basic model (78.8 million), we estimated that 5.5 million medication-related alerts might have been inappropriately overridden, resulting in approximately 196 600 ADEs nationally. This was projected to cost between $871 million and $1.8 billion for treating preventable ADEs. We also estimated that clinicians and pharmacists would have jointly spent 175 000 hours responding to 78.8 million alerts with an opportunity cost of $16.9 million. Discussion and Conclusion These data suggest that further optimization of hospitals computerized provider order entry systems and their associated clinical decision support is needed and would result in substantial savings. We have erred on the side of caution in developing this range, taking two conservative cost estimates for a preventable ADE that did not include malpractice or litigation costs, or costs of injuries to patients.