Depression is a one of the most prevalent psychiatric disorder. Despite several pharmacological treatments, still treating depression is a challenge. Herbal medicine that is better culturally accepted may play an important role in treatment of depression. In this double blind placebo controlled clinical trial, 40 patients that were suffering from major depression according to DSM-IV criteria were randomly allocated to take either fluoxetine and saffron (20 patients) or fluoxetine and placebo (20 patients). The patients of the two groups were evaluated with Beck depression scale at the beginning of the study and after four weeks. Lipid profile (total Triglyceride (TG) level, total cholesterol level, low density lipoprotein (LDL) level and high density lipoprotein (HDL) level) of the patients also was measured at the beginning and end of the trial. 30 patients (19 in saffron group and 11 in placebo group) completed the study. The two groups improved significantly in depression severity at the end of the study without significant difference (P: 0.560). The lipid profile of the two groups did not change significantly. Our study did not demonstrate antidepressive effects for saffron. We did not observe any lipid lowering effect in saffron group too. Of note is that our study is preliminary and larger studies with more patients and longer duration are needed to prove our results.IRCT 2013110915334.