In this study, the protective role of grape seed and skin extract (GSSE) against doxorubicin-induced blood toxicity has been evaluated in rats. Rats were treated with the extract for 8 days and injected with doxorubicin (20 mg/kg) at the 4th day. At the end of the treatment, blood samples were collected for oxidative stress parameters determination and antioxidant enzymes. Doxorubicin increased erythrocytes and plasma malondialdehyde, free iron, H 2 O 2 and carbonylation, decreased calcium and also decreased erythrocytes catalase, peroxidase and superoxide dismutase (specially the Fe isoform). Doxorubicin also decreased plasma catalase and superoxide dismutase (Cu/Zn and Fe isoforms) but increased peroxidase. Doxorubicin increased plasma alanine aminotransferase and aspartate aminotransferase but decreased them within erythrocytes. GSSE co-treatment counteracted almost all deleterious effects induced by doxorubicin. In conclusion, doxorubicin induced a pro-oxidative stress into rat erythrocytes and plasma and GSSE exerted antioxidant properties which can be attributed to free iron and calcium modulation.