OBJECTIVE Medication noncompliance is a significant problem for effective pharmacologic treatment of major depressive disorder (MDD). Attempts to explore predictors of compliance have primarily focused on demographic characteristics; for the most part, these have been shown to be unrelated to compliance. Conversely, the relation between personality characteristics and compliance has been relatively understudied. The primary purpose of this study was to explore the relation between personality characteristics and compliance with antidepressant medication in patients with major depressive disorder (MDD). METHODS Over 14 weeks, we evaluated a sample of outpatients (n = 65) who were receiving antidepressant treatment. We monitored compliance electronically, using the Medication Event Monitoring System. We assessed personality characteristics with the NEO Five-Factor Inventory-Revised. We also assessed depression severity and the frequency and severity of side effects. RESULTS Extraversion was a significant negative predictor of compliance. This was largely explained by the relation between compliance and the Activity facet within Extraversion. We also found a negative relation between the Feelings facet and compliance, while the Modesty facet was a significant positive predictor of compliance with antidepressant medication. Neither severity of depression nor side effects predicted compliance. CONCLUSIONS These results suggest that correlates of personality are important, although frequently ignored, predictors of compliance with antidepressant medication. Identifying predictors of medication compliance may help in the development of individualized treatment regimens and lead to improved therapeutic outcome in the treatment of MDD.