BACKGROUND: Differences in daily utilization of antidepressant therapies may have clinical and economic implications, particularly pharmacy expenditures for health plans. OBJECTIVES: To examine antidepressant daily average consumption (DACON) and drug cost per day for patients with major depressive disorder (MDD) newly initiating serotonin- norepinephrine reuptake inhibitors (SNRIs) or escitalopram. METHODS: A retrospective cohort analysis was conducted in commercially insured patients from July 1, 2008 through June 30, 2009. Patients diagnosed with MDD (ICD-9: 296.2x, 296.3x, or 311) and newly treated with generic desvenlafaxine, venlafaxine XR, duloxetine, or escitalopram were included. For each index medication, DACON was computed for each pill strength by dividing total units dispensed by total days’ supply while the patient persisted on index therapy, then averaging across pill strengths, weighted by days’ supply. Persistence was defined as length of therapy without exceeding a 30-day gap in drug coverage, and drug cost per day was estimated based on standard wholesale acquisition cost. RESULTS: The study population included 1,097 desvenlafaxine, 1,924 venlafaxine XR, 3,216 duloxetine, and 4,730 escitalopram initiators. Average DACON during the study period was significantly lower (P<0.001) for desvenlafaxine (1.04) vs venlafaxine XR (1.43), duloxetine (1.28), or escitalopram (1.07). Average cost per DACON during the study period was significantly lower (P<0.001) for desvenlafaxine ($3.89) vs venlafaxine XR ($6.13) and duloxetine ($5.45), but higher than escitalopram ($3.21). Average persistence (days) was significantly greater for desvenlafaxine (140.6) vs  venlafaxine XR (127.3; P<0.001), duloxetine (133.4; P=0.007), and escitalopram (121.8; P<0.001). CONCLUSIONS: Patients with MDD treated with desvenlafaxine had significantly lower DACON and greater persistence on index antidepressant therapy than patients treated with venlafaxine XR, duloxetine, or escitalopram, and the lowest DACON cost among the SNRIs. Health care decision makers may wish to consider utilization patterns and their economic impact when determining health care policy and treatment decisions.