Whether epigallocatechin-3-gallate (EGCG) regulates the expression of PPARα and the effect of PPARα on EGCG sensitivity. Firstly, CCK-8 kit was used to detect cell viability. Western blotting and real-time PCR was used to measure the protein and mRNA level, respectively. PPARα agonist clofibrate and inhibitor GW6471 were used to alter PPARα expression. Luciferase reporter system and chromatin immunoprecipitation (ChIP) were used to investigate the effect of PPARα on HO-1 expression. EGCG inhibits the viability of cancer cell in a dose-dependent manner. When cancer cells were exposed to EGCG, the expression of PPARα was increased at the protein level in a dose-dependent manner. The PPARα agonist clofibrate attenuated heme oxygenase (HO-1) induction and sensitized cancer cells to EGCG-induced cell death. However, the PPARα inhibitor GW6471 increased HO-1 expression. In vivo chromatin immunoprecipitation (ChIP) confirmed that PPARα interacts with the peroxisome proliferator-responsive sequence of the HO-1 promoter. These results indicate that PPARα is a direct negative regulator of HO-1 activation by EGCG and confers cell susceptibility to EGCG.