Caveolin-1 (Cav-1) is a main structural protein of caveolae and plays important roles in signal transduction and tumorigenesis. We previously showed that Cav-1 was highly expressed in mouse hepatoma cell lines and positively correlated with cell invasion capability. Thus, interfering with the expression and activity of Cav-1 might be a potential way to intervene with hepatoma progression. We used RNA interference to study the biological effects of silencing Cav-1 expression in hepatoma H22 cells, to validate its potential as a therapeutic target. Using small-interfering RNAs (siRNAs) targeting the mRNA region of Cav-1, we effectively suppressed Cav-1 mRNA and protein levels. This resulted in the decreased transformation ability of H22 cells in vitro and in vivo. In addition, downregulation of Cav-1 expression promoted the apoptosis of H22 cells in vitro and in vivo. These results suggest that the use of siRNA could be an efficient molecular therapeutic method for hepatoma with high expression of Cav-1.