BACKGROUND: Renal-origin Ewing's sarcoma is an extremely rare malignancy often misdiagnosed owing to its nonspecific presentation and similarities to other renal tumors. Accurate diagnosis requires a combination of clinical evaluation and advanced diagnostic techniques. Limited case reports make understanding its clinical course and management challenging. This case report aims to raise awareness of renal-origin Ewing's sarcoma, highlight diagnostic challenges, and discuss effective multidisciplinary management strategies to improve patient outcomes. CASE PRESENTATION: A 32-year-old Iranian female patient presented with a chief complaint of progressive dyspnea, anorexia, and night sweating in the last 2 weeks before her admission. Computed tomography scan showed a tumoral lesion in the left kidney with thrombosis extending into the left renal vein and inferior vena cava up to the right atrium. The patient underwent open cardiac surgery and a radical nephrectomy. During surgery, the mass protruded from the inferior vena cava into the right atrium
it was ultimately diagnosed as renal-origin Ewing's sarcoma, and EWSR1 rearrangement was confirmed on pathology. CONCLUSION AND KEY CLINICAL MESSAGE: This case highlights the importance of a thorough diagnostic approach in patients presenting with a renal mass and the value of a multidisciplinary strategy, combining clinical presentation, imaging, histopathology, immunohistochemistry, and molecular studies to achieve an accurate diagnosis. It underscores the critical need for increased awareness and research into the rare entity of renal-origin Ewing's sarcoma, as clinical and pathological information on this condition is limited. Furthermore, this case emphasizes the necessity of timely diagnosis and tailored management to optimize treatment outcomes and improve survival rates in such rare and challenging presentations. CLINICAL TRIAL NUMBER: not applicable.