Abstract Objective The study sought to determine frequency and appropriateness of overrides of high-priority drug-drug interaction (DDI) alerts and whether adverse drug events (ADEs) were associated with overrides in a newly implemented electronic health record. Materials and Methods We conducted a retrospective study of overridden high-priority DDI alerts occurring from April 1, 2016, to March 31, 2017, from inpatient and outpatient settings at an academic health center. We studied highest-severity DDIs that were previously designated as “hard stops” and additional high-priority DDIs identified from clinical experience and literature review. All highest-severity alert overrides (n = 193) plus a stratified random sample of additional overrides (n = 371) were evaluated for override appropriateness, using predetermined criteria. Charts were reviewed to identify ADEs for overrides that resulted in medication administration. A chi-square test was used to compare ADE rate by override appropriateness. Results Of 16 011 alerts presented to providers, 15 318 (95.7%) were overridden, including 193 (87.3%) of the highest-severity DDIs and 15 125 (95.8%) of additional DDIs. Override appropriateness was 45.4% overall, 0.5% for highest-severity DDIs and 68.7% for additional DDIs. For alerts that resulted in medication administration (n = 423, 75.0%), 29 ADEs were identified (6.9%, 5.1 per 100 overrides). The rate of ADEs was higher with inappropriate vs appropriate overrides (9.4% vs 4.3%; P = .038). Conclusions The override rate was nearly 90% for even the highest-severity DDI alerts, indicating that stronger suggestions should be made for these alerts, while other alerts should be evaluated for potential suppression.