Aims: This was a post hoc analysis to determine whether baseline severity of depression influenced the efficacy of duloxetine in treating major depressive disorder (MDD) and to better characterise the symptom response profile for duloxetine in patients with mild, moderate or more severe depression. Methods: Data were pooled from four double-blind, placebo-controlled studies in which outpatients with MDD were randomised to duloxetine (60 mg/day) or placebo for 8-9 weeks. Patients were retrospectively stratified according to baseline 17-item Hamilton Depression Rating scale (HAMD17) total scores: mild = total score ≤ 19 (duloxetine, n = 246; placebo, n = 184); moderate = 20-24 (duloxetine, n = 333; placebo, n = 217); severe = 25+ (duloxetine, n = 127; placebo, n = 87). Results: Duloxetine produced significantly greater baseline-to-end-point improvement vs. placebo (p < 0.05) on the HAMD 17 total score, Maier and retardation subscales, HAMD17 items 1 (depressed mood), 7 (work and activities) and 10 (psychic anxiety) in all three patient cohorts. The largest effect sizes were observed in assessments of core emotional depressive symptoms. A significant improvement for duloxetine vs. placebo was not observed for sleep-related symptoms at end-point or genital symptoms at any time point during acute treatment. With respect to the time course of depressive symptom improvement, the data show that regardless of baseline severity, the most rapid and consistent improvement for duloxetine compared with placebo was observed in the core symptoms of MDD (measured by the Maier subscale). Conclusion: Regardless of baseline MDD severity, duloxetine at one dose (60 mg/day) produced a significant improvement compared with placebo on the core emotional symptoms of MDD. © 2007 The Author.