Objective: To compare clinical characteristics of patients initiating treatment on duloxetine vs. those initiating on venlafaxine XR, escitalopram, and fluoxetine over a two year period. Methods: Retrospective claims analysis of Pharmetrics managed care health plan patients initiating on select antidepressants between September 1, 2004 and August 31, 2006. A total of 798,259 patients were assigned to cohorts based on their most recent antidepressant prescription. Cochran-Mantel-Haenszel test was used to test the proportional differences among the four cohorts. Results: Overall, 72.1% of study patients were female with a mean age of 44.3 years. Demographic differences between cohorts were modest. Based on comparison of medical claims within +/- 30 days of initiation on venlafaxine XR, escitalopram, and fluoxetine, respectively, duloxetine initiators were more likely to have visited a mental health specialist (24.2% vs. 18.2%, 18.6%, and 16.5%) and been diagnosed with depression (29.2% vs. 24.1%, 25.4%, 24.9%). Among the depressed, duloxetine patients were more frequently diagnosed with major depressive disorder (MDD) (52.8% vs. 44.3%, 40.5%, and 36.4%) and, among those diagnosed with MDD, were more frequently diagnosed with recurrent MDD (78.2% vs. 73.8%, 66.2%, and 64.1%). Duloxetine initiators were more frequently diagnosed with a pain condition (44.8% vs. 27.7%, 27.3%, and 24.9%) , particularly for back (15.5% vs. 7.5%, 7.0%, and 6.3%) or musculoskeletal pain (28.2% vs. 15.5%, 14.4%. and 13.1%), and were more likely to have been treated previously with a narcotic analgesic (24.2% vs. 11.1%, 9.8%, and 9.2%) (p <0.05 for all reported differences). Conclusion: Duloxetine patients are more likely to present with more severe depression diagnoses and pain than patients on other antidepressants. Case mix adjustments should be made when comparing outcomes and costs associated with treatment with different antidepressants. These findings are broadly consistent with earlier analyses of data from the first four months following introduction of duloxetine in the U.S.