OBJECTIVES: Major depressive disorder (MDD) is a leading cause of disability, morbidity, and mortality worldwide. The lifetime prevalence in the US is 17%. Treatment resistant depression (TRD) is generally defined as failure to achieve remissions despite adequate treatment. About 30% of patients do not achieve remission after 4 different antidepressant treatment trials (Rush et. Al., 2006). A few studies have examined the economic burden of TRD, but none have investigated the cost associated with more chronic and extensive forms of TRD characterized by non-response to four or more treatment trials. The objective of this study is to compare the direct medical expenditures of TRD patients to chronic MDD patients. METHODS: Patients with chronic MDD (defined as 2 or more years of continuous treatment) and patients with very severe TRD (defined as switching, augmentation, or addition of at least four qualifying therapies) were identified in the PharMetrics Patient-Centric Database.  Medical resource utilization (MRU) and payer costs per patient per year enrolled in the plan were compared.   Patients were matched on duration of enrollment, length of depression, medications taken, and age.  Statistical significance was assessed using Student’s t-tests. RESULTS:   The average medical expenditures per TRD (n=31,803) patient per year enrolled was $12,260 compared to $7,619 for non-TRD chronic MDD patients (n=50,092) (p <0.001), representing 60.9% higher costs per year.  The differences in annual medical expenditures per TRD patient were primarily driven by higher medical and pharmacy MRU (number of services per patient) relative to the chronic MDD group (70.3 vs. 107.6, p <0.001).   CONCLUSIONS: Our results demonstrate that TRD patients accrued significantly higher per patient medical costs than MDD patients due to higher medical resource use. These findings suggest that more effective non-pharmacological alternative interventions are needed.