Purpose: To analyse the role of von Hippel-Lindau (VHL) and transforming growth factor beta-induced (TGFBI) in synergistic mechanisms of 5-aza-2'-deoxycytidine (DAC) and paclitaxel (PTX) against renal cell carcinoma (RCC). Methods: To elucidate the role in the synergy between DAC and PTX against RCC cells, TGFBI expression was regulated using siRNA technology and an expression vector containing the full-length cDNA for TGFBI was also transfected into RCC cells. The proliferation of RCC cells was evaluated using the WST-1 assay and TGFBI expression was detected by real-time PCR (RT-PCR), and Western blot. Results: The results indicated that the expression of TGFBI was significantly decreased by DAC or PTX alone in vitro and in vivo. Moreover, the combination of DAC and PTX caused a synergistic decrease in the expression of TGFBI in RCC cells. We also investigated the effect of VHL-TGFBI signaling on the synergy between DAC and PTX, although the synergy between the two medications was not abolished by interfering with VHL activity or TGFBI expression. RCC cells without VHL activity and RCC cells expressing high levels of TGFBI displayed an increased synergistic effect compared to control cells. Conclusion: Our study suggests that VHL-TGFBI signaling is involved in the synergy between DAC and PTX against RCC cells. In addition, the synergy between DAC and PTX is more effective in VHL inactive RCC cells.