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Major depressive disorder is a devastating mental illness leading to a lifetime prevalence of higher than 16% on individuals. The treatment delay and inevitable adverse effects are major limitations of current depression interventions. Emerging evidence indicates that curcumin produced significant antidepressant properties in depression in both rodents and humans without adverse effects. Therefore, it is necessary to further clarify the antidepressant actions of curcumin and the underlying mechanism in depressed patients. A total of 108 male adults aged between 31 and 59 years were systematically recruited in Tianjin Anding Hospital. Subjects were administered the Chinese version of 17-item Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale that measures different scores of depressive symptoms. The subjects were asked to take 2 capsules containing either 1000 mg of curcumin or placebo soybean powder daily for 6 weeks on the basis of their current antidepressant medications. The plasma levels of interleukin 1β, tumor necrosis factor α, brain-derived neurotrophic factor, and salivary cortisol were measured by enzyme-linked immunosorbent assay before and after curcumin or placebo treatment during the 6-week procedure. Chronic supplementation with curcumin produced significant antidepressant behavioral response in depressed patients by reduction of 17-item Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale scores. Furthermore, curcumin decreases inflammatory cytokines interleukin 1β and tumor necrosis factor α level, increases plasma brain-derived neurotrophic factor levels, and decreases salivary cortisol concentrations compared with placebo group. These findings indicate the potential benefits of further implications of supplementary administration of curcumin to reverse the development of depression and enhance the outcome of antidepressants treatment in major depressive disorder.