Context: Saffron (Crocus sativus L.) has been used as a cuisine spice in eastern and western societies for thousands of years. In traditional medicine, saffron is recommended for the treatment of various kinds of disorders including heart palpitations. Objective: We investigated the hypothesis of the protective effect of saffron on lethal cardiac arrhythmias induced by heart ischemia-reperfusion in rat. Materials and methods: Animals were divided into a control (CTL) group that received tap water, Saf50, Saf100 and Saf200 groups that were orally treated with aqueous extracts of saffron, at dosages of 50, 100 and 200 mg/kg/day, respectively, and amiodarone (Amio) group that orally received 30 mg/kg/day for seven days. On day 8, heart ischemia-reperfusion was induced by ligation and releasing of the left anterior descending coronary artery. Results: During reperfusion, the numbers and durations of ventricular fibrillation (VF) decreased in all groups compared to the CTL group (p50.05). Ventricular tachycardia (VT)/VF numbers (3.2 AE 1.2), durations (4.9 AE 2.6) and also arrhythmia severity (1.9 AE 0.35) were decreased significantly in the Saf100 group versus CTL group values (18.4 AE 11.6, 52 AE 31 and 3.3 AE 0.3, respectively). The PR and QTcn intervals of ECG were significantly longer in the Saf200 group (p50.001 versus CTL). The other doses of saffron only significantly prolonged the QTcn interval. Conclusion:The results suggest that pretreatment with saffron, especially at the dosage of 100 mg/kg/day, attenuates the susceptibility and incidence of fatal ventricular arrhythmia during the reperfusion period in the rat. This protective effect is apparently mediated through reduction of electrical conductivity and prolonging the action potential duration.