Background: CTC and ctDNA-based, actionable genomic alterations are being increasingly utilized for precision oncology therapies. However, the concordance of genomic alterations in CTC DNA vs. ctDNA is not established. Methods: After CTC/ctDNA isolation, we performed whole genome copy number alteration (CNA) analysis in 88 men with mCRPC treated with enzalutamide (E) or abiraterone acetate (A) (n = 72), and radium-223 (n = 16). We performed comparative genomic hybridization (aCGH) and low-pass whole genome sequencing (~0.1x, lpWGS) for CNA assessment and evaluated the concordance between gains/losses in matched CTCs, ctDNA and germline DNA in 63 samples; 32 from 16 men receiving radium-223, and 31 from 16 men receiving E/A. Results: Of the 88 enrolled men with mCRPC, 51% had ≥5 Cellsearch CTCs. We identified common genomic gains in 63 CTCs and matched ctDNA in FOXA1 (56 vs. 75%), KDM6A (51 vs. 21%), AR (48 vs. 64%), MYCN (30 vs. 5%), and MYC (18 vs. 24%). Common copy losses included ZFHX3 (60 vs. 44%), FGFR2 (43 vs. 32%), PHLPP1 (33 vs. 33%), BRCA1 (29 vs. 30%), and RB1 (13 vs. 21%). We analyzed AR copy gain status in 21 ctDNA specimens by aCGH and lpWGS, finding a concordance of 89%; detection correlated with high ctDNA content and CTC number. However, we found only 33% AR gain concordance in 38 CTC aCGH samples vs ctDNA lpWGS samples, and 63% AR gain concordance for CTC aCGH vs. ctDNA aCGH samples collected at the same time points. In 63 matched CTCs and ctDNA samples, we observed high concordance in gain of FOXA1 (91%) and AR (63%), moderate concordance for gain of MYC (55%), NCOR2 (41%), loss of ZFHX3 (53%) and PHLPP1 (48%), but low concordance for gain of KDM6A (25%) and loss of BRCA1 (39%), RB1 (38%), and FGFR2 (37%). Conclusions: Detection of genomic alterations at the whole genome level is feasible in ctDNA and CTC DNA and concordance across ctDNA platforms was high. However, we found variable concordance in CTC DNA vs. ctDNA copy number alterations depending on the specific gene, type of alteration, ctDNA concentration, and CTC enumeration likely reflecting biologic variability or differences in assay sensitivity. Clinical trial information: NCT02269982, NCT02204943