OBJECTIVES: Treatment adherence for a sufficient duration is important in the treatment of major depressive disorder (MDD). This study examined the association between treatment persistence with duloxetine and health care costs in the year after medication initiation. METHODS: In a large U.S. commercial managed-care claims database, 4542 patients (18 to 64 years old) with at least 1 claim with a diagnosis of MDD (ICD-9-CM: 296.2 and 296.3) were initiated on duloxetine during 2006. Patients were included if they had no active prescription of duloxetine during the 6 months prior to initiation and had continuous enrollment for 12 months prior to and post-duloxetine initiation. Treatment persistence was defined as the length of therapy without exceeding a 30-day gap. A general linear model regression was performed to examine the associations between treatment persistence and healthcare costs in the post 1 year. RESULTS: Overall, average length of duloxetine therapy was 116.0 days (SD=63.5) in the post 6 months; 62.8% of patients stayed on the medication for more than 3 months. Significant associations between persistence and healthcare costs were observed. With prolonged length of therapy (<31 days, 31-90 days, >90 days), average total health care costs were significantly reduced ($25,499, $18,438, and $17,255, p=.020). Specifically, medical costs were significantly reduced ($21,338, $14,123, and $11,496, p=0.009), while pharmacy costs were increased ($4,161, $4,316, and $5,759, p<0.001). After adjustment for baseline demographics, comorbid conditions, and health care costs, results were essentially unchanged. Adjusted total healthcare costs were $20,162, $13,821, and $13,706 for patients who stayed on the medication for <31 days, 31-90 days, and >90 days, respectively. CONCLUSIONS: Medical treatment costs in the year after initiation on duloxetine decreased by a greater amount among duloxetine patients with greater persistence compared to those who discontinued early. The findings underscore the importance of sufficient length of therapy for major depressive disorder.