OBJECTIVE: The study sought to determine availability and use of structured override reasons for drug-drug interaction (DDI) alerts in electronic health records. MATERIALS AND METHODS: We collected data on DDI alerts and override reasons from 10 clinical sites across the United States using a variety of electronic health records. We used a multistage iterative card sort method to categorize the override reasons from all sites and identified best practices. RESULTS: Our methodology established 177 unique override reasons across the 10 sites. The number of coded override reasons at each site ranged from 3 to 100. Many sites offered override reasons not relevant to DDIs. Twelve categories of override reasons were identified. Three categories accounted for 78% of all overrides: will monitor or take precautions, not clinically significant, and benefit outweighs risk. DISCUSSION: We found wide variability in override reasons between sites and many opportunities to improve alerts. Some override reasons were irrelevant to DDIs. Many override reasons attested to a future action (eg, decreasing a dose or ordering monitoring tests), which requires an additional step after the alert is overridden, unless the alert is made actionable. Some override reasons deferred to another party, although override reasons often are not visible to other users. Many override reasons stated that the alert was inaccurate, suggesting that specificity of alerts could be improved. CONCLUSIONS: Organizations should improve the options available to providers who choose to override DDI alerts. DDI alerting systems should be actionable and alerts should be tailored to the patient and drug pairs.