OBJECTIVES: Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed antidepressants. This claims database study compared healthcare resource use and costs among patients with major depressive disorder (MDD) treated with vilazodone, versus other SSRIs. METHODS: Adults with an MDD diagnosis and ≥1 prescription fill for vilazodone, citalopram, escitalopram, fluoxetine, paroxetine or sertraline were identified from the Truven Health MarketScan^®Research Databases (January 1, 2010 to December 31, 2012). Patients who concomitantly used adjunctive medication, either a second-generation antidepressant or antipsychotic, were excluded. All-cause and MDD-related healthcare resource use and costs (measured from a payer’s perspective in 2012 US dollars) over a 6 month period post-index date were compared among treatment groups using multivariate robust Poisson regression and robust linear regression, respectively, adjusted for age, gender, insurance type, index year, comorbidities, prior antidepressant treatment, and pharmacy copayment at baseline (12 months pre-index date). RESULTS: The study cohort included 49,861 patients (mean age: 44.0 years; 70% female). Compared with the vilazodone cohort (N=3,527), patients in the citalopram (N=12,187), escitalopram (N=8,275), fluoxetine (N=10,142), paroxetine (N=3,146), and sertraline (N=12,584) cohorts had significantly more all-cause inpatient (IP) visits, length of IP stay and emergency room (ER) visits, and MDD-related IP visits and length of IP stay following the index date, after adjusting for baseline characteristics. All-cause medical service costs (IP + outpatient + ER) were significantly higher across all other SSRI cohorts versus vilazodone by $758 to $1,165 (P<0.05). Similarly, all-cause total costs were also significantly or numerically higher across all SSRI cohorts versus vilazodone by $351 to $780 after accounting for prescription costs. CONCLUSIONS: MDD treatment with vilazodone was associated with significantly lower rates of inpatient and emergency services, and with significantly lower all-cause medical service and numerically lower total costs to payers compared to other SSRIs included in this study.