Depression is a major worldwide health problem. Indeed, by 2020, depressive disorders are estimated to represent the second largest disease burden worldwide. Although a variety of pharmaceutical agents are available for the treatment of depression, psychiatrists find that many patients cannot tolerate the side effects, do not respond adequately, or finally lose their response. Our objective was to assess the efficacy of petal of Crocus sativus in the treatment of mild-to-moderate depression in a 6-week double-blind, placebo-controlled and randomized trial. Forty adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition for major depression based on the structured clinical interview for DSM IV participated in the trial. In this double-blind, placebo-controlled and randomized trial, patients were randomly assigned to receive capsule of petal of C. sativus 30 mg/day (BD) (Group 1) and capsule of placebo (BD) (Group 2) for a 6-week study. At 6 weeks, petal of C. sativus produced a significantly better outcome on Hamilton Depression Rating Scale than placebo (d.f.=1, F=16.87, p<0.001). There were no significant differences in the two groups in terms of observed side effects. The results of this study indicate the efficacy of petal of C. sativus in the treatment of mild-to-moderate depression. A large-scale trial is justified.