There is ongoing debate regarding the effectiveness of antidepressants in patients with milder major depressive disorder (MDD). This post-hoc analysis evaluated the efficacy and tolerability of duloxetine in the subset of 159 (75 duloxetine and 84 placebo) patients with milder MDD (baseline HAMD17 total score > or = 15 and < or = 18) who were treated once daily with duloxetine 60 mg or placebo in two identical, 9-week, randomised, double-blind trials. At endpoint, change from baseline on HAMD17 was greater in the duloxetine group (-7.0) than in the placebo group (-4.1) (p = 0.005). Response and remission rates, and improvement on the Clinical Global Impressions-Severity (CGI-S) scale, the Patient Global Impressions-Improvement (PGI-I) scale, and measures of painful symptoms were also significantly better in the duloxetine group (p < 0.05). Tolerability was consistent with that seen in previous studies of duloxetine in patients with more severe depression. In conclusion, duloxetine 60 mg/day is effective and well tolerated in milder MDD.