We investigated the molecular mechanisms by which 5-aza-2 '-deoxycytidine (DAC) and paclitaxel (PTX) use lymphoid enhancer-binding factor 1 (LEF1) and the Wnt/beta-catenin pathway to synergistically interact against renal cell carcinoma (RCC). LEF1 expression was examined by real-time PCR and immunohistochemistry. The regulation of LEF1/beta-catenin protein expression by DAC and/or PTX was examined by Western blot and immunoprecipitation. To analyze the effect of LEF1 on the proliferative ability of RCC cells and the synergy of DAC and PTX against RCC cells, an expression vector containing the full-length cDNA for LEF1 was transfected into RCC cells, and LEF1 expression was also decreased using siRNA technology. Our results confirmed that DAC and PTX synergistically decreased the expression of LEF1 in vivo and in vitro. Moreover, treatment of RCC cell lines with the combination of DAC and PTX caused a synergistic decrease in LEF1/phospho-beta-catenin. Our study also demonstrated a negative correlation between LEF1 expression and the proliferative ability of RCC cells. Although interfering with LEF1 expression did not abolish the synergy between the two agents, RCC cells expressing high levels of LEF1 displayed an increased synergistic effect compared with RCC cells expressing low levels of LEF1. This study suggests that LEF1 can enhance the proliferation of RCC cells and that the LEF1/beta-catenin complex plays an important role in the synergy of DAC and PTX against RCC cells. Moreover, the synergy between DAC and PTX may be more effective in RCC cells expressing high levels of LEF1. Crown Copyright (C) 2011 Published by Elsevier Ireland Ltd. All rights reserved.