The aim of this study was to examine the association between duloxetine adherence/persistence and hospital utilization. In a managed care claims database, 8521 patients with a major depressive disorder diagnosis were initiated on duloxetine in 2006. Patients had no active duloxetine prescription for 6 months before initiation and had continuous enrollment for 12 months preinitiation and postinitiation. Adherence was defined as medication possession ratio of 0.8 or more, and persistence was defined as the duration of therapy without exceeding a 30-day gap. Logistic regression and negative binominal regression were conducted. Overall, 55.8% of patients were adherent and the average duration of duloxetine therapy was 118.4 days within 6 months after initiation. Adherent patients had significantly lower rates of hospitalization (19.7 vs. 23.4%, P<0.0001) and emergency room visits (30.6 vs. 36.9%, P<0.0001) than nonadherent patients. Hospitalization and emergency room visits were significantly reduced with treatment persistence (P<0.0001). After adjustment for demographics, comorbidities, and prior hospitalization, adherence was associated with reduced hospitalization (odds ratio=0.86) and emergency room visits (odds ratio=0.80). Patients on duloxetine of more than 90 days, compared with less than 31 days, were 16% less likely to be hospitalized and 22% less likely to have emergency room visits. Duloxetine adherence and persistence appear to be associated with reduced hospital utilization in the 1-year follow-up period.