Genetic instability is a hallmark of human cancers. It is the driving force for tumor development as it facilitates the accumulation of mutations in genes that regulate cell death and proliferation and therefore promotes malignant transformation. Chronic inflammation is a common underlying condition for human tumor development, accounting for approximately 20% of human cancers. TNFα is an important inflammation cytokine and is crucial to the development of inflammation-associated cancers. We have shown that TNFα can cause DNA damages through reactive oxygen species (ROS). TNFα treatment in cultured cells resulted in increased gene mutations, gene amplification, micronuclei formation and chromosomal instability. Antioxidants significantly reduced TNFα-induced genetic damage. In addition, TNFα treatment alone led to increased malignant transformation of mouse embryo fibroblasts, which could be partially suppressed by antioxidants. Therefore, genetic instability plays an important role in inflammation-associated cancers.