The correct risk categorization and staging of upper tract urothelial cancer (UTUC) is key for disease management. Computed tomography urography (CTU) and urinary cytology have limited accuracy for risk stratification of UTUC. Ureteroscopy may increase the risk of bladder recurrence. Recently, Bladder EpiCheckTM (EpiCheck) showed a high accuracy in the detection of bladder cancer. The aim of the study is to investigate the diagnostic accuracy of EpiCheck in the clinical management of UTUC and to compare it with urinary cytology. In this single-arm blinded prospective single-center study (02/2019-12/2020), all patients candidates to ureteroscopy for suspicion of UTUC were included. Bladder and upper urinary tract (UUT) samples were collected before ureteroscopy to test for cytology and Epicheck. EpiCheck accuracy was calculated in bladder and UUT samples and compared to cytology. EpiCheck resulted diagnostic in 83/86 (97%) and 73/75 (97%) of UUT and bladder samples. Histology was positive in 47/83 (57%) and 42/73 (58%) cases, respectively. In UUT samples, EpiCheck yielded a sensitivity/specificity/NPV/PPV of 83/79/77/84% vs 59/88/61/87% of cytology. The sensitivity/NPV for high-grade tumors was 96%/97% for EpiCheck vs 71%/86% for cytology. EpiCheck indicated ureteroscopy in 45/80 (56%) patients, missing 17%/4% of all/high-grade UTUC with 9% of unnecessary URS. In bladder samples, the sensitivity/NPV for high-grade tumors was 71/88% for EpiCheck and 59%/87% for cytology. Epicheck may be an important tool to decrease number of unnecessary URS. The clinical implementation of EpiCheck in UTUC warrants further investigation in multicentric prospective randomized trials.