Background: Approximately 15% of men with newly diagnosed prostate cancer (PCa) have high-risk features, which increase the risk of recurrence. Better predictive biomarkers, such as circulating tumor cells (CTCs), could allow for earlier detection of biochemical recurrence. Here, we aim to evaluate the ability to detect CTCs using an enrichment free, unbiased CTC identification technology from men with high risk, localized PCa after radical prostatectomy (RP) and correlate their presence with prospective clinical data. Methods: Blood samples of 31 patients with high risk, localized PCa obtained 2-4 months post RP were shipped to Epic Sciences on an IRB approved protocol. All nucleated cells were subjected to immunofluorescent (IF) staining for cytokeratin (CK), CD45, and AR N terminus. CTCs were identified by fluorescent scanners using algorithmic analysis. CK expressing (CK⁺) CTCs were enumerated and analyzed for AR expression and individually sequenced for copy number variation (CNV) and large scale transition (LST, a surrogate of genomic instability). Patients were followed prospectively for biochemical recurrence, defined as detectable PSA. Progression free survival was calculated using Kaplan-Meier and Cox proportional hazards. Results: CTCs were detected in 87.1% (27/31) samples with an average of 5.6 CTCs/ml (range: 0 – 22.87) detected per patient. AR expression was detected in 12.9% (4/31) of patients. Ninety-nine CTCs from 14 patients were amenable to LST and CNV sequencing and analyses. 10.1% (10/99) CTCs from 7 patients exhibited higher ( > = 6) LSTs than control WBCs (95% WBCs had LST < 6). Copy number alterations were identified in CTCs in commonly mutated genes in PCa, including AR, MYC, and TP53 amplification and deletions in PTEN and RB1. Patients with higher CTC burdens exhibited a trend toward shorter PFS (hazard ratio: 1.65; 95% CI: 0.7-3.86; p: 0.13). Conclusions: There was a high incidence of CTC detection after RP in patients with high risk, localized PCa. We observed a trend toward shorter PFS in those with higher CTC burden and genomic alterations detectable in CTCs are consistent with established CNAs in PCa. Tissue genomic correlatives are under analysis.