Immune checkpoint inhibitors have shown promising efficacy in multiple cancer types. The recent food and drug administration approval of PD-1 inhibitors for mismatch repair (MMR)-deficient tumors has extended use of these treatments to all cancer types, and programmed death ligand 1 (PD-L1) positivity in tumor tissue has also been shown to predict susceptibility to immunotherapy. Despite these advances, the response to immunotherapy in endometrial cancer remains poorly understood. Here, we describe the case of a patient with MMR-proficient, PD-L1-negative stage IV endometrial cancer who exhibited a strong clinical response to combination PD-1 and CTLA-4 inhibition. She showed deep and durable ongoing partial response to nivolumab and ipilimumab that has persisted after 12 months. This case indicates the potential existence of an endometrial cancer subtype that is sensitive to immune checkpoint blockade based on mechanisms other than those driven by MMR deficiency or PD-L1 positivity. Improved understanding of immunotherapy in advanced endometrial cancer is clearly needed and offers the potential to significantly enhance patient outcomes.