The proinflammatory cytokine tumor necrosis factor-α (TNF-α) was originally considered to have activity against malignant disease. However, recent studies suggest TNF-α may also act as an endogenous tumor promoter. In the present work, mice deficient in TNF-α either genetically (TNF-α^−/−) or after blockade with a neutralizing antibody (cV1q) were used to investigate the role of TNF-α in skin tumor development. Papillomas were induced in wild-type (wt) mice after treatment of skin with the initiating agent 9,10-dimethyl-1,2-benzanthracene followed by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 15 weeks. TNF-α^−/− mice were resistant to papilloma development when compared with wt mice on C57Bl/6J, 129/SvEv, and BALB/c genetic backgrounds. Primary murine keratinocytes (newborn keratinocytes) and skin homogenates were used to characterize TPA-stimulated TNF-α expression. TPA induced TNF-α protein in newborn keratinocytes in vitro and epidermis in vivo. Neutralization of TNF-α protein with cV1q in vivo for 0–15 weeks of promotion significantly decreased skin tumor development after 9,10-dimethyl-1,2-benzanthracene/TPA treatment. cV1q treatment during the early stages of tumor promotion (0–6 weeks) was equally effective. These data suggest that early induction of TNF-α is critical for skin tumor promotion. cV1q also reduced TPA-stimulated expression of matrix metalloproteinase 9 and granulocyte macrophage colony-stimulating factor, proteins that are differentially regulated in wt and TNF-α^−/− epidermis. Treatment of the 410.4 transplantable breast carcinoma with cV1q reduced tumor growth in vivo, illustrating that inhibition of tumor growth through neutralization of TNF-α is not limited to skin carcinogenesis. These results provide further evidence for procancer actions of TNF-α and give some rationale for use of TNF-α antagonists in cancer prevention and treatment.