HDAC6, a member of histone deacetylation family, is reported to play critical roles in transcription regulation, cell cycle progression, and cancer development. However, the expression status and significance of HDAC6 in hepatocellular carcinoma (HCC) is still controversial, and little is known about the role of HDAC6 in HCC angiogenesis and the correlation between expression of HDAC6 and prognosis of HCC patients with liver transplantation (LT). Our experiments showed HDAC6 was significantly downregulated in HCC tissues (P = 0.025), and low expression of HDAC6 was found to be closely associated with recurrence (P = 0.006), and could predict poor recurrence-free survival (P = 0.047) for HCC patients with LT. Moreover, knockdown of HDAC6 could promote HUVEC migration, proliferation, and tube formation in vitro, and suppress HCC cell apoptosis, and promote HCC cell proliferation in hypoxia. Remarkably, knockdown of HDAC6 could significantly up-regulate the expression of HIF-1α and VEGFA in vivo and in vitro, which facilitated HIF-1α mediated angiogenesis in HCC. Further study showed that HDAC6 was down-regulated under hypoxia in a time dependent manner. Hence, the present findings suggested a role for suppression of HDAC6 in promoting the angiogenesis in HCC by HIF-1α/VEGFA axis. HDAC6 may serve as a recurrence predictive factor for HCC after LT and pharmacological or genetic activation of HDAC6 could be a novel anti-angiogenesis approach for HCC therapy. © 2015 Wiley Periodicals, Inc.