OBJECTIVE: The optimal adjuvant therapy for women with stages III and IV endometrial cancer following surgical staging and cytoreductive surgery is controversial. We sought to determine the outcome of patients with advanced stage endometrial cancer treated with postoperative chemotherapy ±radiation to determine whether there was an advantage to combining treatment modalities. METHODS: A retrospective analysis of patients with surgical stages III and IV endometrial cancer from 1975 to 2006 was conducted at Duke University and the University of North Carolina. Inclusion criteria were comprehensive staging procedure including hysterectomy, bilateral salpingo-oophorectomy, ± selective pelvic/aortic lymphadenectomy, surgical debulking, and treatment with adjuvant chemotherapy and/or radiotherapy. Progression-free (PFS) and overall survival (OS) were analyzed using Kaplan–Meier method and Cox proportional hazards model. RESULTS: 356 Patients with advanced stage endometrial cancer were identified who received postoperative adjuvant therapies; 48% (n = 171) radiotherapy alone, 29% (n = 102) chemotherapy alone, 23% (n = 83) chemotherapy and radiation. The median age was 66 years; 38% had endometrioid tumors; and 83% were optimally debulked. There was a significant difference between the adjuvant treatment groups for both OS and PFS (p < 0.001), with those receiving chemotherapy alone having poorer 3-year OS (33%) and PFS (19%) compared to either radiotherapy alone (70% and 59%) or combination therapy (79% and 62%). After adjusting for stage, age, grade, and debulking status the hazard ratio (HR) for OS was 1.60 (95% CI, 0.88 to 2.89; p = 0.122) for chemotherapy alone and 2.01 (95% CI, 1.17 to 3.48; p = 0.012) for radiotherapy alone, compared to combination therapy. When the analysis was restricted to optimally debulked patients the adjusted HR for patients who were treated with either chemotherapy or radiation alone indicated a significantly higher risk for disease progression [HR = 1.84 (95% CI, 1.03 to 3.27; p = 0.038); HR = 1.80 (95% CI, 1.10 to 2.95; p = 0.020)] and death [HR = 2.33 (95% CI, 1.12 to 4.86; p = 0.024); HR = 2.64 (95% CI, 1.38 to 5.07; p = 0.004)], respectively, compared to patients who received combination therapy. CONCLUSION: Combined adjuvant chemotherapy and radiation was associated with improved survival in patients with advanced stage disease compared to either modality alone. Future clinical trials are needed to prospectively evaluate multi-modality adjuvant therapy in women with advanced staged endometrial cancer to determine the appropriate sequencing and types of chemotherapy and radiation.