We report a rare case of urothelial carcinoma (UC) of the renal pelvis with trophoblastic differentiation that occurred in a 55-year-old male patient. The patient presented with gross hematuria and paroxysmal lumbago pain 5 months ago. The enhanced computed tomography (CT) scan demonstrated a large space occupying lesion in the left kidney and multiple retroperitoneal lymph node enlargements. Histologically, high-grade infiltrating urothelial carcinoma (HGUC) contained giant cells which were positive for beta-human chorionic gonadotropin (β-hCG). Three weeks after resection, positron emission tomography and computed tomography (PET-CT) scan showed multiple nodules of metastasis in the left renal region, extensive systemic muscle, bone, lymph node, liver and bilateral lung metastases. The patient underwent bladder perfusion chemotherapy and gemcitabine combined with cisplatin chemotherapy regimens. This is the eighth documented case of UC of the renal pelvis with trophoblastic differentiation. Due to its rarity and extremely poor prognosis, it is important to clarify the characteristics of the disease and make an accurate and prompt diagnosis.