Caveolin-1 is the principal components of caveolae membranes, implicated in oncogenesis and angiogenesis. Until now, its expression and functional significance in hepatocellular carcinoma (HCC) are still unclear. In the present study, we demonstrated that expression of caveolin-1 was markedly upregulated in HCC patients. In addition, increased caveolin-1 expression correlated positively with the histological differentiation, portal venous invasion, hepatic venous invasion, intrahepatic metastases, and recurrence, suggesting a role for caveolin-1 in the progression of HCC. HepG2 cell line was transfected with pcDNA3.1/caveolin-1 to observe the significance of the change in caveolin-1 expression. We showed that caveolin-1 overexpression could not only protect HepG2 cells from apoptosis but also enhance its migration and invasion by upregulating MMP-2, MMP-9, and VEGF expressions. Collectively, our clinical and in vitro data indicate that the status of caveolin-1 expression may be one of causative factors for the invasion and poor prognosis in HCC.