OBJECTIVES: Prescribing an initial optimum therapeutic dose while avoiding dose-related side effects is important in the treatment of major depressive disorder (MDD). Many factors may influence a physician’s decision on an antidepressant choice and starting dose. The purpose of the present study was to identify the pretreatment predictors of initial high-dose prescription of duloxetine in patients with MDD in real world clinical settings. METHODS: A total of 10,128 patients with MDD who were selected from a large commercially administrative claims database and were initiated on duloxetine between July 1, 2005 and June 30, 2006 were included in the analysis. Patients had no prescriptions of duloxetine in the 6 months prior to duloxetine treatment. For patients who had continuous enrollment for 12 months prior to duloxetine treatment, the associations between demographic characteristics and pre-initiation clinical variables in the prior 1 year and initial high-dose (>60 mg/day) prescription compared with average dosage (60 mg/day) prescription were examined by logistic regression. RESULTS: Of the sample, 31.2% were initially prescribed duloxetine less than 60 mg/day; 62.1%, 60 mg/day; and 6.8%, >60 mg/day. Compared with average-dose patients, high-dose patients had more comorbidities; used more benzodiazepine, anxiolytics, atypical antipsychotics, lithium, psychostimulants, and anticonvulsants; and used more medical care services with higher pharmacy and medical costs in the prior 1 year. After adjustment for health plan type and geographic region of residence, the following factors were independently associated with initial high-dose prescription: prior use of psychostimulants (OR= 1.45), no prior use of selective serotonin reuptake inhibitors (OR=1.28), physician specialty (psychiatrist vs. non-psychiatrist, OR=1.43), and high medical cost in the prior 1 year (OR=2.12). CONCLUSIONS: Multiple demographic and clinical characteristics and prior health care service utilization are associated with initial high-dose duloxetine prescription. High-dose patients may represent a group of complex patients with high medical cost who need intensive medical intervention.