OBJECTIVES:  Antidepressants are among the most common prescription drugs taken by Americans. However, some antidepressants can cause clinically significant drug-drug interactions. The study aims to examine the prevalence and factors associated with potential drug-drug interactions of antidepressants in U.S. outpatient settings. METHODS: This project proposed a secondary data analysis using the 2012 National Ambulatory Medical Care Survey (NAMCS) conducted by the National Center for Health Statistics. All patient visits with at least one antidepressant prescription were included. Drug-drug interaction was defined according to Drug Interaction Facts. A series of weighted descriptive analyses were performed to evaluate the prevalence of potential drug interactions. A multivariate logistic regression was developed to examine how patient characteristics impact the presence of drug interactions. Receiver operating characteristic (ROC) curve was used for assessing the discrimination in the proposed logistic regression model. RESULTS:  Approximately 93.7 million antidepressants were prescribed in US outpatient settings including selective serotonin re-uptake inhibitors (SSRI) (63.2 million), atypical antidepressants (20.4 million), tricyclic antidepressants (TCA) (10.1 million), etc. Among these, 6.9% of them had at least one potential major or moderate drug interaction. The most frequent drugs interacting with antidepressants were: sertraline, fluoxetine, venlafaxine, oxycodone, citalopram, etc. The results of multivariate logistic regression showed that there was a significantly increased likelihood of encountering drug interactions in relationship with patient’s age, race, and number of medication used(P<0.001). The area under the ROC curve was computed as 0.61, corresponding to the logistic regression model with moderate discrimination. CONCLUSIONS:  Unfortunately, drug-drug interaction can be difficult to remember and are commonly missed. However, its adverse effects can lead to morbidity or even mortality if appropriate clinical actions are not taken. As with all perspectives in pharmacovigilance, when determining the relevance and significance of the choice of drugs, considering patient’s individual characteristics is of the utmost importance.