Locally advanced endometrial cancer is associated with high-risk of both local pelvic and systemic recurrence. Radiotherapy has been traditionally used after surgery in this patient population, however the substantial risk of systemic metastases undermines clinical outcomes of women treated with local modality treatment alone. Thus, combination chemo-radiotherapy seems a logical approach aiming to reduce the risk of both local and distant failure. Investigated in multiple institutional and cooperative group trials, the use of chemoradiation in this patient group yields failure-free survival rates exceeding 60% at three years. However, patients treated with this approach pay a high price in both acute and late toxicity. In a recently reported randomized phase III trial, use of single chemotherapy strategy was less toxic and not inferior to the combined chemoradiotherapy approach. Based on this evidence, systemic chemotherapy alone is the preferred treatment strategy for women with stage III endometrial cancer.