The objective of this paper is to better understand the relationship of pain and mood in patients with fibromyalgia and comorbid major depressive disorder (MDD). Pooled data from 4 double-blind, placebo-controlled, randomized trials of duloxetine hydrochloride 60-120 mg/day in patients with fibromyalgia were included (N = 1332). Of these, 350 (26% [147 placebo, 203 duloxetine]) had comorbid MDD (per Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision criteria) and were included in these analyses. Primary measures included Brief Pain Inventory average pain; Hamilton Depression Rating Scale or Beck Depression Inventory. Logistic regression was used to evaluate the consistency of treatment effect across various subgroups. Path analysis was used to assess the effect of duloxetine on improvement in pain in the presence of improvement in mood and vice versa. Results indicated that 69% of improvement in pain was a direct effect of treatment, with improvement in mood accounting for 31% of pain response. In conclusion, consistent with our hypothesis, duloxetine produced a substantial direct effect on pain improvement and change in mood exerted a modest indirect effect on pain improvements in patients with fibromyalgia and MDD. Hence, both direct and indirect analgesic and antidepressant properties appear to be relevant for the treatment of these comorbid patients with duloxetine. © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.