Background: Recent studies have indicated potential of saffron for applying in a wide variety of diseases such as psychiatric and neurologic disorders. The concurrent use of saffron with SSRIs can lead to reducing the dose of SSRIs. Saffron at a dose of 200 mg may change some hematological and biochemical parameters. Objective: The goal of this trial was to assess the safety of concomitant administration of saffron and SSRI in patients with major depressive disorder (MDD). Methods: Twenty adult outpatients between 18 to 55 years-old with the diagnosis of MDD who were receiving an SSRI for at least 1 month prior to the initiation of the study entered this double-blind trial. They were randomly assigned to receive capsule of saffron (15 mg twice daily) or placebo. Some laboratory parameters were measured at baseline and week 4 of the study. Other side effects checked on a prepared list of side effects, were systematically recorded throughout the study at baseline and on a weekly basis. Results: Saffron as an add-on medication to SSRIs for 4 weeks did not cause any statistically significant changes in laboratory parameters including AST, ALT, ALP, BUN, Cr., FBS, TG, TC, WBC, RBC, Hgb, Ht, PT, INR, and Pl count. Conclusion: This preliminary study provides safety evidences of concurrent intake of saffron and SSRI.