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Introduction: Crocus sativus L. (saffron) has many biological effects such as antioxidant property. The present study investigated the immunomodulatory effects of the aqueous saffron extract on streptozotocin (STZ)-induced diabetic rats. Materials and methods: In this study, the rats were divided into the following groups of 9 animals each: control, untreated diabetic, three saffron extract-treated diabetic groups. Diabetes was induced by STZ in rats. Saffron was administered 3 days after STZ administration; these injections were continued to the end of the study (4 weeks). At the end of the 4-week period, blood was drawn for biochemical assays and the abdominal aorta was removed for detecting the inflammatory cytokines expression. Results: We found that saffron decreased blood glucose, malondialdehyde, nitric oxide, total lipids, triglycerides, cholesterol levels significantly (p < 0.01) and increased glutathione level, catalase, and superoxide dismutase activities in the saffron-treated diabetic groups compared with the untreated groups, in a dose dependent manner (p < 0.05, p < 0.01, p < 0.001). On the other hand, saffron-treated diabetic rats inhibited the expression of inflammatory cytokines in the abdominal aorta versus the untreated diabetic rats. Conclusion: Our results validate the use of saffron as a treatment against diabetes mellitus and its vascular complications.