We have shown previously that endogenous deficiency of interleukin (IL)-12 promotes photocarcinogenesis in mice. To characterize the role of IL-12 deficiency in tumor angiogenesis, we developed IL-12p35 knockout (IL-12 KO) mice on a C3H/HeN background. IL-12 KO mice and their wild-type (WT) counterparts were subjected to a photocarcinogenesis protocol. When tumor yield was stabilized, samples of tumor and tumor-uninvolved UVB-exposed skin were collected and subjected to immunohistochemistry, gelatinolytic zymography, real-time PCR, and Western blot analysis of angiogenic factors. We found that the protein, mRNA expression and/or activity of the matrix metalloproteinases (MMP)-2, MMP-3, MMP-7, and MMP-9, and basic fibroblast growth factor, which play crucial roles in tumor growth, were significantly higher in UVB-exposed skin and tumors of IL-12 KO mice compared with WT mice. With respect to the tumor vasculature, the expression of CD31-positive cells and the expression of vascular endothelial growth factor were higher in the tumors of IL-12 KO mice than WTs. The proliferative capacity of tumor cells of the IL-12 KO mice was significantly higher than their WT counterparts when determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and by analyzing the expression of cyclin D1. The level of the proinflammatory cytokine IL-6 and the expression of IL-23 in tumors of IL-12 KO mice were markedly higher than in the tumors of WT mice. IL-23 has been shown to promote tumor growth. Together, these data indicate for the first time that IL-12 deficiency promotes proangiogenic stimuli in UVB-induced skin tumors and suggest that endogenous enhancement of IL-12 levels may be effective in the prevention and treatment of UV-induced skin cancers. ©2007 American Association for Cancer Research.