Clinical Decision Support (CDS) systems can alert physicians about potential clinical risks and suggest suitable treatment alternatives at appropriate times in the health care process. We evaluated the frequency with which physicians overrode medication alerts and the override reasons provided. Data obtained from primary care practices affiliated with two Harvard teaching hospitals were downloaded. Physicians overrode more than half of CDS medication alerts, with formulary, age-based, and renal substitutions the most likely. Many drug-drug and drug-allergy interactions overridden had the potential to cause patient harm.