Major depressive disorder (MDD) is a leading cause of disability, morbidity, and mortality worldwide. The lifetime prevalence in the United States is estimated at 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. A few studies have examined the economic burden of TRD, but none has investigated the cost associated with more chronic and extensive forms of TRD characterized by nonresponse to ≥4 treatment trials.The objective of this study was to compare the health care utilization (HCU) and direct medical expenditures of TRD patients with those of chronic MDD patients.Patients with chronic MDD (defined as ≥2 years of continuous treatment) and patients with TRD (defined as undergoing at least 4 different qualifying antidepressant therapy trials) were identified in the PharMetrics Patient-centric Database. The association between TRD and medical expenditures was measured by using multivariate regression analysis.The classification of TRD had a clinically meaningful and statistically significant association with increased medical expenditures. Holding all else equal, the classification of TRD was associated with a 29.3% higher costs (P < 0.001) in medical expenditures compared with patients not meeting the study definition of TRD.These results demonstrate that TRD is associated with significantly higher per-patient medical costs due to higher HCU. The findings suggest that the development of treatment alternatives for TRD is warranted. Limitations related to the use of secondary administrative data are noted.