Cyclophosphamide (CYP), is a well-known alkylating agent used as antitumor drug. Acute lung and liver injury occur in virtually all patients treated by CYP. The present study was conducted to examine the possible activity of antioxidants like 6-proanthocyanidin, melatonin and vitamin É on treatment of lung and liver injury induced by CYP. Acute lung and liver injuries were induced by a single I.P. dose (75 mg/kg) of CYP. Mice treated with CYP showed a significant increase in lung and liver lipid peroxide (MDA), decrease in reduced glutathione (GSH) in both lung and liver and a decrease in liver SOD activity. In addition CYP produced a significant reduction in blood catalase activity, lymphocyte count and marked increase in blood neutrophils. Liver injury can be manifested also through a significant increase in ALT values and AP levels. Moreover pathological examination helps to manipulate the severity of lung and liver damage. Administration of proanthocyanidin (400 mg/kg) orally normalized all the measured parameters when compared to CYP alone. Melatonin administration (14 mg/kg) orally was capable also to normalize all the measured parameters except blood catalase activity. Vitamin E (50 mg/kg) orally produced no significant increase in liver GSH, both blood catalase and AP activities when compared to CYP group. In conclusion, treatment with the previous mentioned antioxidants corrected the majority of changes in almost all biochemical markers like (MDA, SOD, GSH, ALT and AP levels) that were changed after CYP injection. Blood catalase activity, as well as blood neutrophils, lymphocytes count and histopathological changes associated with CYP returned back similar to the control group. Also we found that proanthocyanidin is the most effective antioxidant in treatment of acute lung and liver injury induced by CYP when compared with melatonin and vitamin E.