Bone is one of the most frequent targets of small cell lung cancer (SCLC) metastasis and is closely associated with a poor prognosis, but the specific cellular gene alterations responsible for SCLC with bone metastasis are unclear. Zinc finger E‐box binding homeobox 1 (ZEB1) as an E‐box transcriptional repressor has been suggested that an important inducer of the epithelial‐mesenchymal transition (EMT) and a promoter of tumor metastasis in colon, breast and lung cancers. However, the relationship between ZEB1 and SCLC with bone metastasis is unclear. In this study, ZEB1 was found to be highly expressed in bone‐metastatic SCLC tissues and cell lines as compared with those that were non‐metastatic (P < 0.05). Using a lentivirus RNA interference technique to knockdown ZEB1 expression in bone‐metastatic SCLC cells (SBC‐5 cell line), we found that ZEB1 siRNA could inhibit the invasive and migratory ability and decrease parathyroid hormone‐related protein expression, as determined by invasion assays and enzyme‐linked immunosorbent assays. Besides, ZEB1 siRNA significantly inhibited the bone metastasis of SBC‐5 cells in vivo. Furthermore, overexpression of ZEB1 in SBC‐3 cells, which demonstrate promoted bone‐metastatic potential, dramatically promoted their invasive and migratory ability and parathyroid hormone‐related proteinexpression as well as increased the number and sites of bone metastases in vivo compare to the control group. We also found that SBC‐3 cells underwent EMT, as indicated by decreased epithelial markers and increased mesenchymal marker expression. Taken together, these results indicate that ZEB1 promoted the invasive ability and bone metastasis of SCLC cells, and that this was partially mediated via the EMT pathway. (Cancer Sci, doi: 10.1111/j.1349‐7006.2012.02347.x, 2012)