Nickel has been known to represent a lethal toxicity to human under environmental exposure. Particulary, nickel accumulation is able to cause oxidative DNA damage and tumor development. Redox imbalance by oxidative stress is rescued via modulation by redox factors which can scavenge excessively produced reactive oxygen species (ROS). Thioredoxin reductase 1 (Trr 1) is one of major redox factors having a potential role in cellular defense system against oxidative stress. In this study, we investigated whether Trr 1 has protective roles against nickel-induced oxidative stress and genotoxicity using ROS measurement, comet and micronucleus (MN) assay. We found significant increase of intracellular ROS generation in nickel- treated Trr 1 defective cells compared with Trr 1 proficient cells. In addition, under nickel treatment, Trr 1 knockdown cells showed higher amount of DNA strand breaks as oxidative DNA damage rather than in Trr 1 wild type cells. Moreover, MN as a crucial biomarker for carcinogenicity was remarkably induced in the nickel-exposed Trr 1 silencing cells. Therefore, these results might provide novel insight on the role of Trr 1 in cellular protection from environmental nickel-induced genotoxicity. In conclusion, we emphasized the synergistic toxicity of Trr 1 knockdown and environmental nickel exposure in relevance to gene-environment interactions.