Interleukin-12 (IL-12)-deficiency promotes photocarcinogenesis in mice; however, the molecular mechanisms underlying this effect have not been fully elucidated. Here, we report that long-term exposure to ultraviolet (UV) radiation resulted in enhancement of the levels of cell survival kinases, such as phosphatidylinositol 3-kinase (PI3K), Akt (Ser(473)), p-ERK1/2, and p-p38 in the skin of IL-12p40 knockout (IL-12 KO) mice compared with the skin of wild-type mice. UV-induced activation of nuclear factor-kappaB (NF-kappaB)/p65 in the skin of IL-12 KO mice was also more prominent. The levels of NF-kappaB-targeted proteins, such as proliferating cell nuclear antigen (PCNA), cyclooxygenase-2, cyclin D1, and inducible nitric oxide synthase, were higher in the UV-exposed skin of IL-12 KO mice than the UV-exposed skin of wild types. In short-term UV irradiation experiments, subcutaneous treatment of IL-12 KO mice with recombinant IL-12 (rIL-12) or topical treatment with oridonin, an inhibitor of NF-kappaB, resulted in the inhibition of UV-induced increases in the levels of PCNA, cyclin D1, and NF-kappaB compared with non-rIL-12- or non-oridonin-treated IL-12 KO mice. UV-induced skin tumors of IL-12 KO mice had higher levels of PI3K, p-Akt (Ser(473)), p-ERK1/2, p-p38, NF-kappaB, and PCNA and fewer apoptotic cells than skin tumors of wild types. Together, these data suggest that the loss of endogenous IL-12 activates survival signals in UV-exposed skin and that may lead to the enhanced photocarcinogenesis in mice.