OBJECTIVES: To identify patients with treatment-resistant depression (TRD) using the Massachusetts General Hospital (MGH) claims signature and examine healthcare costs. METHODS: This retrospective study identified patients 18-64 years with an antidepressant medication claim (index date) and at least two ICD-9-CM codes for depression.  Patients were excluded if they had any other psychiatric disorder. Each patient was assigned an MGH score, a validated measure of depressive severity, based on points associated with utilization of electroconvulsive therapy (ECT), antidepressants and adjunctive therapies (atypical antipsychotic, mood stabilizer, stimulant) within two years following index date. An MGH score of ≥ 3.5 signified TRD. For patients with an additional year of pharmacy and medical coverage (i.e., 3 years following index date), direct medical costs (hospitalizations, office visits, emergency department visits and prescription medications) were calculated.  RESULTS: The cohort consisted of 20,089 patients with a mean [SD] age of 42.7 [11.3] years and 72.6% women. Only 0.09% of patients had an ECT claim while 28.6% of patients had at least one prescription claim for an adjunctive therapy (24.0% for atypical antipsychotics, 13.3% for mood stabilizers and 14.6% for stimulants). TRD (i.e., MGH score ≥ 3.5) was identified in 31.2% of patients. Cost data was available for 18,720 patients and showed a mean 16.5% increase in cost for each 1 point increase in MGH score.  Patients with TRD had a mean $2,274 higher annual direct medical costs, a 45% increase in costs, compared with non-TRD patients (i.e., MGH score < 3.5). CONCLUSIONS: Using a claims signature, we found a high prevalence and cost of TRD in a commercial managed care organization. Identifying patients is an important step in addressing the burden of TRD. Future research should determine effective interventions which improve clinical remission rates in this patient population.