Extracellular superoxide dismutase (EC-SOD) overexpression modulates cellular responses such as tumor cell suppression and is induced by $IFN{gamma}$. Therefore, we examined the role of EC-SOD in $IFN{gamma}$-mediated tumor cell suppression. We observed that the dominant-negative protein kinase C delta ($PKC{delta}$) suppresses $IFN{gamma}$-induced EC-SOD expression in both keratinocytes and melanoma cells. Our results also showed that $PKC{delta}$-induced EC-SOD expression was reduced by pretreatment with a PKC-specific inhibitor or a siRNA against $PKC{delta}$. $PKC{delta}$-induced EC-SOD expression suppressed cell proliferations by the up-regulation of p21 and Rb, and the downregulation of cyclin A and D. Finally, we demonstrated that increased expression of EC-SOD drastically suppressed lung melanoma proliferation in an EC-SOD transgenic mouse via p21 expression. In summary, our findings suggest that $IFN{gamma}$-induced EC-SOD expression occurs via activation of $PKC{delta}$. Therefore, the upregulation of EC-SOD may be effective for prevention of various cancers, including melanoma, via cell cycle arrest.