CIRP has been implicated in apoptosis, yet its mechanism of action remains unknown. To determine the role of CIRP in DNA damage-induced apoptosis, we performed CIRP overexpression and knockdown experiments to investigate the effects of CIRP on key molecules in apoptosis pathway. Etoposide treatment was used to induce DNA damage-induced apoptosis. We found that CIRP knockdown increased p53 level, which in turn up-regulated pro-apoptotic genes and down-regulated anti-apoptotic genes. In contrast, CIRP overexpression decreased p53 level, which in turn down-regulated pro-apoptotic genes and up-regulated anti-apoptotic genes. The change in the expression levels of pro-apoptotic and anti-apoptotic genes shifts the balance between life and death of cells. CIRP expression is upregulated by chronic inflammation, and this phenomenon provides an interesting interventional opportunity in cancers arising from chronic inflammation. Chronic inflammation up-regulates CIRP, which in turn inhibit apoptosis. Therefore, inhibiting the function of up-regulated CIRP may have a therapeutic value in cancer.