TGFβ is known to transactivate EGFR. However, the signaling component involved in this crosstalk has yet to be revealed. Here, we found that TGFβ 1 phosphorylated EGFR in a dose-dependent manner in SCC13 and A431 cells, and it was not blocked by EGF-neutralizing antibody. H 2 O 2 was increased by TGFβ 1 treatment in the same time-kinetics as EGFR activation. Pretreatment of N-acetyl cysteine abolished TGFβ 1 -induced H 2 O 2 induction and EGFR activation. Direct treatment of H 2 O 2 phosphorylated EGFR and catalase inhibitor prolonged TGFβ 1 -induced EGFR activation. These results show that TGFβ 1 activates EGFR via an H 2 O 2 -dependent mechanism, which subsequently leads to the activation of Erk 1/2 .