Recent studies have demonstrated that a caspase-activated deoxyribonuclease (CAD) causes DNA degradation in nuclei after treatment of cells with caspase-3. In this study, we evaluated the effect of CAD overexpression on tumor cells treated with a chemotherapeutic agent in vitro and in vivo. In an in vitro study, we transfected mouse fibroblast L cells with a vector encoding mouse CAD and evaluated the therapeutic potential of CAD gene transfer to L cells treated with cisplatin (CDDP). In an in vivo study, percutaneous transfer of the mouse CAD gene by particle-mediated (gene gun) delivery caused overexpression of CAD in mouse squamous cell carcinoma (SCC). Our results showed that a combined treatment of CDDP and exogenous introduction of the CAD gene into tumor cells in vitro and in vivo arrested tumor growth and induced apoptosis. These results suggest that combined treatment of CDDP and exogenous CAD expression might be a useful strategy for cancer therapy.