Abstract: Background and Objectives: Doxorubicin is an efficient anti-neoplastic drug but its clinical usefulness is limited by its serious adverse effects such as cardiotoxicity. The main objective of this research was to investigate whether natural marine astaxanthin could chemosensitize the Ehrlich ascites carcinoma cells to the anti-tumor effect of doxorubicin. Materials and Methods: Survival of Ehrlich ascites carcinoma bearing mice was used as model to evaluate the chemosensitizing effect of astaxanthin to doxorubicin cytotoxicity. After treatment with doxorubicin and/or astaxanthin, doxorubicin uptake was measured by spectrofluorometric assay, apoptosis and the cell cycle phase distribution were determined by flow cytometry analysis and P53 gene expression was also studied in the EAC cells. Results: Treatment of tumor bearing mice with doxorubicin showed a significant increase in the mean survival time to 32.5 days with 30% long-term survivor. Treatment of the tumor-bearing animals with astaxanthin and doxorubicin showed a significant increase in the mean survival time to 41.1 days with 80% long-term survivor. Doxorubicin cellular uptake was increased significantly after astaxanthin treatment. Moreover, astaxanthin treatment dramatically increased the early apoptosis and G2/M phase accumulation after addition to doxorubicin. P53 gene expression was up regulated after doxorubicin treatment, moreover addition of astaxanthin synergized the action of doxorubicin where p53 gene expression was highly upregulated. Conclusion: The present study concluded that the marine astaxanthin potentiates the cytotoxic activity of doxorubicin against the growth of mammary tumor cells in vivo through accumulation of the tumor cells in G2/M phase , induction of apoptosis and up regulation of the tumor suppressor p53 gene expression.