Abstract Background: Circulating tumor cells (CTCs) are an established prognostic marker in castration-resistant prostate cancer but have received little attention in localized high-risk disease. We studied the detection rate of CTCs in patients with high-risk prostate cancer before and after androgen deprivation therapy and radiotherapy to assess its value as a prognostic and monitoring marker.Patients and Methods: We performed a prospective analysis of CTCs in the peripheral blood of 65 treatment-naïve patients with high-risk prostate cancer. EpCAM-positive CTCs were enumerated using the CELLSEARCH system at 4 timepoints. A cut off of 0 vs ≥ 1 CTC/7.5 ml blood was defined as a threshold for negative versus positive CTCs status.Results: CTCs were detected in 5/65 patients (7.5%) at diagnosis, 8/62 (12.9%) following neoadjuvant AD, and 11/59 (18.6%) at the end of radiotherapy, with a median CTC count/7.5 ml of 1 (range, 1-136). Only 1 patient presented a positive CTC result 9 months after radiotherapy. Positive CTC status was not significantly associated with any clinicopathologic factors. However, a significant association was observed between conversion of CTCs and stages T3 ( P = 0.044) and N1 ( P = 0.002). Detection of CTCs was not significantly associated with overall survival ( P > 0.40).Conclusions: We found a low detection rate for CTCs. De novo positive CTC counts after treatment are probably due to a passive mechanism associated with destruction of the tumor. Further studies with larger samples and more accurate assessment methods are needed to determine the prognostic and therapeutic potential of CTC detection.Trial registration: ClinicalTrials.gov ID: NCT01800058