Clusterin/apolipoprotein J (Clu) is a ubiquitously expressed secreted heterodimeric glycoprotein that is implicated in several physiological processes. It has been reported that the elevated level of secreted clusterin (sClu) protein is associated with poor survival in breast cancer patients and can induce metastasis in rodent models. In this study, we investigated the effects of sClu inhibition with small interfering RNAs (siRNAs) on cell motility, invasion, and growth in vitro and in vivo. MDA-MB-231 cells were transfected with pSuper-siRNA/sClu. Cell survival and proliferation were examined by 3-(4,5-dimethyl-thiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and clonogenic survival assay. The results showed that sClu silencing significantly inhibited the proliferation of MDA-MB-231 cells. The invasion and migration ability were also dramatically decreased, which was detected by matrigel assays. TUNEL staining and caspase-3 activity assay demonstrated that sClu silencing also could increase the apoptosis rate of cells, resulting in the inhibition of cell growth. We also determined the effects of sClu silencing on tumor growth and metastatic progression in an orthotopic breast cancer model. The results showed that orthotopic primary tumors derived from MDA-MB-231/pSuper sClu siRNA cells grew significantly slower than tumors derived from parental MDA-MB-231 or MDA-MB-231/pSuper scramble siRNA cells, and metastasize less to the lungs. These data suggest that secretory clusterin plays a significant role in tumor growth and metastatic progression. Knocking-down sClu gene expression may provide a valuable method for breast cancer therapy.