Background: Analysis of somatic genomic alterations in primary tumors is often used to define mutational status and guide therapeutic decisions. Selective pressures (including multiple lines of therapy) can lead to tumor evolution through step-wise accumulation of genomic alterations. CTCs from mCRPC pts have shown phenotypic heterogeneity in size, shape, CK expression (exp) and AR exp. Heterogeneity increases with multiple lines of therapy and is associated with treatment resistance. Defining CTC genotype to phenotype correlation may enable identification of emerging resistant clones for which a change in tx may be needed. We performed NGS whole genome CNV analysis at the single CTC level to detect driver somatic alterations associated with CTC epithelial & AR exp profiles. Methods: 147 CTCs were individually sequenced from 9 mCRPC pt blood samples and classified as traditional, CK-, or small CTCs and analyzed for AR exp. CTCs were individually isolated, lysed, WGA, library constructed, sequenced, aligned, parsed, normalized, and subtracted from germline CNV. Each pt CTC CNV profile was used to identify distinct sub-clonal populations and characterize CTC genomes. The genomic alterations were associated with CTC phenotypes. Results: Within each pt, 2-5 clonal populations were identified. On average, 11 CNV events were detected per CTC, with an intra-patient CTC correlation of 30-59%. The correlation increased 33% within a CTC specific phenotype (p = 0.013). The presence of mCRPC driver alterations (Amp- AR, cMYC; Del- TP53, PTEN, RB1) were predominantly in CTC subpopulations of pts not responding to tx. Overall, 59% of CTCs had a single driver alteration. Conclusions: Tracking all CTC populations is important to assessing genomic driver alterations. Intra-patient CTC genomic heterogeneity is common and statistically associated with heterogeneity of size, shape, CK & AR exp. CK- & small CTCs, unlike traditional CTCs, often possess loss of tumor suppressors, and are associated with resistance. Actionable alterations may only be observed in rare CTC subtypes and represent a potential new target to delay disease progression.