Depression is a serious disorder in today's society, with estimates of lifetime prevalence as high as 21% of the general population in some developed countries. As a therapeutic plant, saffron is considered excellent for stomach ailments and as an antispasmodic, to help digestion and to increase appetite. It is also used for depression in Persian traditional medicine. Our objective was to assess the efficacy of the stigmas of Crocus sativus (saffron) 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, 4th edition for major depression based on the structured clinical interview for DSM IV participated in the trial. Patients had a baseline Hamilton rating scale for depression score of at least 18. In this double-blind, placebo-controlled, single-centre and randomized trial, patients were randomly assigned to receive a capsule of saffron 30 mg[sol ]day (BD) (Group 1) or a capsule of placebo (BD) (Group 2) for a 6-week study. At 6 weeks, Crocus sativus produced a significantly better outcome on the Hamilton depression rating scale than the placebo (d.f. = 1, F = 18.89, p < 0.001). There were no significant differences in the two groups in terms of the observed side effects. The results of this study indicate the efficacy of Crocus sativus in the treatment of mild to moderate depression. A large-scale trial is justified. Copyright 2005 John Wiley & Sons, Ltd.