Abstract Biopsies of HCC can be technically difficult, given the vascular nature of the liver and underlying liver disease. Many HCC patients do not get biopsies, and molecular characterization of these tumors is not possible. Capture of CTCs from blood allows for analysis of cancer cells in metastatic dissemination. The use of EpCAM-based enrichment platforms limits the type of tumor cells that can be recovered, as it selects only for cells which express the antigen of interest. Nonselective methods of CTC analysis are needed. An ongoing study is evaluating the recovery of CTCs in HCC patients with elevated serum alpha-fetoprotein (AFP) using the novel antibody-independent ApoStream™ platform, which utilizes the principle of dielectrophoretic field-flow fractionation to position cells in a hydrodynamic flow profile for sorting. Paired blood samples from HCC patients were analyzed by CellSearch and ApoStream™. Collected cells were immunophenotyped using antibodies against Cytokeratin (CK), CD45, DAPI, and AFP, and analyzed by quantitative laser scanning cytometry. In comparison with the CellSearch platform, ApoStream™ isolated higher number of CK+/CD45-/DAPI+ CTCs in HCC cancer patients. A majority of the CK+/CD45-/DAPI+ CTCs enriched by the ApoStream™ platform (62-98%) were AFP+. ApoStreamTM also isolated AFP+, putative CTCs with the CK-/CD45-/DAPI+ phenotype (9-85 cells), and cells with CK+/CD45+/DAPI+ phenotype (1-978 cells). Conclusion: The ApoStreamTM CTC enrichment platform successfully isolated a greater number of CTCs from HCC patients. ApoStream™ CTC analysis is also being used for pharmacodynamic analysis in an ongoing phase I study of the combination of sorafenib and vorinostat in patients with advanced HCC. In preclinical models, the combination synergistically induces tumor cell death through activation of CD95. In this study, CTC analysis will compare the expression of CD95 and other markers prior to and after drug combination exposure. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2381. doi:1538-7445.AM2012-2381