OBJECTIVES: Adherence and persistence with prescribed medication is important in the treatment of major depressive disorder (MDD). This study compared adherence and persistence of 3 branded antidepressants (duloxetine, venlafaxineXR, and escitalopram) and generic selective serotonin reuptake inhibitors (SSRIs) in the real-world treatment of MDD. METHODS: A total of 44,026 MDD patients (18 to 64 years) from a large commercial administrative claims database were classified as initiators of duloxetine (n=7,567), venlafaxine XR (n=6106), escitalopram (n=10,239), or generic SSRIs (n=20,114) during the calendar year 2006. Patients who had used the same antidepressant in the 3 months prior to initiation date were excluded. Adherence was defined as the medication possession ratio (MPR) ≥0.8, and persistence was defined as the length of therapy without exceeding a 15-day gap in the post 1 year. Pair-wise comparisons were performed with and without adjustment for demographic and clinical covariates. RESULTS: Adherence rate in the post 1 year was significantly higher in duloxetine recipients (38.1%) than those patients treated with venlafaxine XR (34.0%), escitalopram (25.4%), or generic SSRIs (25.5%) (all p values <.01). Duloxetine recipients stayed on the medication longer (158.5 days) than those who received venlafaxine XR (149.6 days), escitalopram (129.1 days), or generic SSRIs (130.2 days) (all p values <0.01). Compared with patients treated with escitalopram or generic SSRIs, venlafaxine XR recipients had better adherence and longer persistence (p<0.01). After adjustment for baseline demographics, prior medications, and comorbid conditions, duloxetine still had better adherence and longer persistence than venlafaxine XR, with escitalopram and generic SSRIs having lower adherence and persistence. CONCLUSIONS: Duloxetine-treated patients may have better adherence and longer stay on the medication than those patients treated with venlaxafine XR, escitalopram, or generic SSRIs. Further research is needed to examine clinical and economical benefits of adherence and persistence with antidepressant therapy.