Purpose: C-X-C chemokine receptor type 4 (CXCR4) is known to be involved in both developmental and adult angiogenesis; however, its role in tumor angiogenesis remains largely unknown. Here, the role of vascular CXCR4 in regulating vascular structure in hepatocellular carcinoma (HCC) was assessd, and the clinical value of CXCR4 was explored. Experimental Design: The expression of CXCR4 in HCC was determined by IHC and immunofluorescence. Characteristics of CXCR4(+) cells were determined by in vitro and mice experiments. Kaplan-Meier survival analysis was used to determine the correlation of CXCR4 expression with prognosis. Results: We found that CXCR4 is selectively expressed on a fraction of tumor endothelial cells (TECs) in HCC tissues, but not on the hepatic endothelium in peritumoral area. High levels of CXCR4 on TECs tended to develop a sinusoidal vasculature in tumors and predicted poor prognosis for patients with HCC. CXCR4(+) endothelial cells (EC) displayed the functional features of tip cells, with increased expression of tip cell-related markers. Functional studies revealed that CXCR4 could directly promote vessel sprouting in vitro and in vivo. Interestingly, sorafenib treatment reduced the frequency of CXCR4(+) ECs in culture and inhibited the formation of sinusoidal vasculature and growth of CXCR4(High) xenograft tumors. Moreover, high CXCR4 vascular density in resected tumor tissues before sorafenib treatment was associated with prolonged survival in patients with advanced HCC treated with sorafenib. Conclusions: These data revealed that CXCR4 is a novel HCC vascular marker for vessel sprouting and could serve as a potential therapeutic target and a predictive factor for sorafenib treatment in patients with HCC. (C) 2017 AACR.