Abstract. Endometrial cancer (ECa) is the fourth most common malignancy in women. Currently, there is no effective therapy for advanced and recurrent cancer. Among the pooroutcome endometrial cancers, there is a high frequency of TP53 mutations. We have previously reported that amifostine has a direct anti-cancer effect and has a significant synergistic effect with paclitaxel when used in endometrial cancer cell and xenograft models. In this report, using a cell line with knock-down p53 expression through siRNA, we found that amifostine enhancement of paclitaxel's anticancer effect is p53 status-dependent. Amifostine promotes entry into the G2-M phase through regulation of cyclin-dependent kinase-1 activity in cells with dysfunctional p53, thereby enhancing cancer cell sensitivity to paclitaxel. The synergistic effect between amifostine and paclitaxel was further confirmed in vivo using xenografts created with primary patient tumor tissue. Sensitivity to the therapeutic effect of paclitaxel in combination with amifostine was dependent upon the status of p53. A tumor with a nonsense TP53 mutation showed increased therapeutic response to paclitaxel and amifostine as measured by tumor weight compared to a tumor with wildtype TP53. Our study provides a rationale for a clinical trial of combined paclitaxel and amifostine in endometrial cancer patients whose tumors harbor TP53 mutations.