OBJECTIVE To investigate the role of transforming growth factor-beta-induced (TGFBI) in metastasis of renal cell carcinoma (RCC) and the associations between TGFBI expression and von Hippel-Lindau (VHL) status. METHODS In null type VHL cells stably transfected with the VHL vector, the expression of VHL in cells with wild type VHL was decreased by siRNA. We investigated the effects of hypoxia-inducible transcription factor (HIF) on TGFBI in RCC cells by decreasing the expression levels of HIF-1 Phi and HIF-2 alpha through siRNA. The secretion of transforming growth factor-beta 1 (TGF-beta 1) in RCC cells with different VHL status was analyzed by enzyme-linked immunosorbent assay. The role of TGFBI in metastasis and the effect of VHL activation on TGFBI-induced adhesion, migration, and invasion in RCC cells were examined using matrigel, chemotaxis, and the transwell system, respectively. RESULTS Our results suggested that TGF-beta 1 and TGFBI might be targets of VHL, and the suppression of TGFBI by VHL is not by way of the HIF-1 alpha or HIF-2 alpha pathway. The expression of TGFBI was significantly enhanced by TGF-beta 1 in VHL-inactive RCC cells compared with VHL-active cells. In addition, these results indicate that TGFBI participated in the adhesion, migration, and invasion of RCC cells, which are dependent on the inactivation of VHL. CONCLUSION The results of the present study suggest that TGFBI-promoted metastasis of RCC cells depends on inactivation of the VHL tumor suppressor and that TGFBI could be a therapeutic target against RCC in the future. UROLOGY 79: 966.e1-966.e7, 2012. Crown Copyright (C) 2012 Published by Elsevier Inc.