Scorpion envenomation is a main general health problem in developing countries, especially in tropical and subtropical regions. Hemiscorpius lepturus as a member of the Hemiscorpiidae family is cause of the most scorpion sting lethality in Iran. In the present study, the oxidative stress and antioxidant defense in serum of envenomated sheep with the venom of Hemiscorpius lepturus were investigated. Nine sheep were randomly divided into three groups (three in each). Groups A, B and C received 0.10, 0.05 and 0.01 mg kg-1 of H. lepturus venom subcutaneously, respectively. Blood sampling were performed 30 min before envenomation (control) and 30 min, 1, 2, 3 and 6 hr after envenomation and serum levels of total antioxidant capacity (TAC), malonedialdehyde (MDA) and protein carbonyl (PCO) were determined. The TAC was significantly increased at the doses of 0.10 mg kg-1 (at 3 hr) and 0.05 mg kg-1 (at 6 hr) compared to pre-injection time. However, no significant differences were observed in serum levels of MDA and PCO in different groups. It can be concluded that the dose of 0.01 mg kg-1 of venom had no effect on stress factors of serum, but according to increased level of TAC at the doses of 0.05 and 0.10 and no significant changes in serum levels of MDA and PCO, the oxidative damage has been prevented by the antioxidant defense system response.