Peroxiredoxin I (Prx I), an antioxidant enzyme, has multiple functions in human cancer. However, the role of Prx I in hepatic tumorigenesis has not been characterized. Here we investigated the relevance and underlying mechanism of Prx I in hepatic tumorigenesis. Prx I increased in tumors of hepatocellular carcinoma (HCC) patients that aligned with overexpression of oncogenic H-ras. Prx I also increased in H-rasG12V transfected HCC cells and liver tumors of H-rasG12V transgenic (Tg) mice. When Prx I was knocked down in HCC-H-rasG12V cells, cell colony formation significantly diminished compared with controls. Null mutation of Prx I in H-rasG12V Tg mice showed significantly reduced tumor formation compared with H-rasG12V Tg mice that was associated with downregulation of pERK and cyclin D1. Whereas pERK and cyclin D1 increased in HCC-H-rasG12V cells overexpressing Prx I and hPrx I transfected HCC cells and the expression of pERK and PCNA was also increased in liver tumors, compared with non-tumor of H-rasG12V Tg mice, indicating that Prx I maybe involved in hepatic tumorigenesis, In Prx I deficient H-rasG12V Tg mice, reactive oxygen species (ROS) level was higher and induced more increased DNA damage and cell death than in H-rasG12V Tg mice especially over 7 months. In this study, Prx I was found to be transcriptionally regulated by Nrf2 which was activated by the H-rasG12V/pERK/FoxM1 pathway. In conclusion, Prx I suppresses ROS-induced hepatic cancer cell death and forms a positive feedback loop with the Ras/ERK/FoxM1/Nrf2 pathway to promote hepatic tumorigenesis.