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The purpose of this study was to evaluate the impact of circulating tumor cells (CTCs) as a prognostic marker in patients with high-risk non–muscle-invasive bladder cancer (NMIBC) and assess the efficacy and reliability of 2 different CTC isolation methods.Globally, 155 patients with a pathologically confirmed diagnosis of high-risk NMIBC were included (pT1G3 with or without carcinoma in situ) and underwent transurethral resection of bladder tumor (TURB) after a blood withdrawal for CTC evaluation. A total of 101 patients (Group A) had their samples analyzed with the CellSearch automated system, and 54 (Group B) had their samples analyzed with the CELLection Dynabeads manual system.Patients were followed for 28 months, and during this interval, there were a total of 65 (41.9%) recurrences, 27 (17.4%) disease progressions, and 9 (5.8%) lymph node and/or bone metastasis. In our CTC analysis, there were 20 (19.8%) positive patients in Group A and 24 in Group B (44.4%). In our analysis, we found a strong correlation between CTC presence and time to first recurrence; in Group A, we observed an incidence of recurrence in 75% of CTC-positive patients and in Group B of 83% of CTC-positive patients. The time to progression was also strongly correlated with CTCs: 65% and 29%, respectively, of those patients who progressed in those with CTCs in Group A and B.The study demonstrates the potential role of CTCs as a prognostic marker for risk stratification in patients with NMIBC, to predict both recurrence and progression.Circulating tumor cells (CTCs) could represent a promising, noninvasive prognostic and predictive marker in high-risk patients with non–muscle-invasive bladder cancer. We retrospectively evaluated 155 patients with pT1G3 bladder cancer who underwent transurethral resection of bladder tumor after a blood withdrawal for CTC evaluation. In our analysis, the presence of CTCs was significantly associated with time to first recurrence and time to progression.