Background: Cyclophosphamide is a chemotherapeutic agent used for treatment of leukemia, lymphoma and myeloma. Several studies reported wide range of cyclophosphamide induced cardiotoxicity in cancerous patients. Alpha lipoic acid is a natural antioxidant used widely for prevention and treatment of different conditions.  Aim of the work: This work was conducted to study the role of alpha lipoic acid in cyclophosphamide induced cardiotoxicity basing on histological and ultrastructural studies.  Material and Methods: Forty-four adult male Albino rats were divided into four groups: group I (control), group II (alpha lipoic acid -treated) in a dose (25 mg/kg body weight/day) given orally, group III (cyclophosphamide -treated) in a dose (200 mg/kg body weight) single dose injected intraperitoneally and group IV (alpha lipoic acid plus cyclophosphamid-treated). The experiment was conducted for ten days. Cardiac muscle specimens were subjected to light, electron microscopic and immunohistochemical study.  Results: Microscopic examination of cardiac muscle of cyclophosphamide treated group (III) showed focal disruption and vacuolation of cardiac muscle fibers with mononuclear infiltration between cardiac muscle fibers. Ultrastructurally, destruction of myofibrils, swollen, irregular arranged mitochondria and dilated SER were noted. Some nuclei showed chromatolysis and others were heterochromatic with irregular nuclear membrane. These results were confirmed by significant decrease in Bcl2. The intercellular spaces were wide contained dilated congested blood vessels and collagen. Alpha lipoic acid administration improved cardiac muscle architecture but still not attained the complete normal morphology  Conclusion: Supplementation of alpha lipoic acid in concomitant with cyclophosphamide (CYP) can ameliorate the CYP induced cardiac injury.