Ultraviolet (UV) B irradiation of the skin induces acute inflammation, as characterized by erythema, edema, and immunosuppression, and is subsequently linked to the progression of skin cancer. Toll-like receptor 4 (TLR4), a component of innate immunity, has been shown to play an important role in cancer. To elucidate the role of TLR4 in UVB-induced tumor development, TLR4-proficient (C3H/HeN) and TLR4-deficient (C3H/HeJ) mice were exposed to multiple doses of UVB radiation (200 mJ/cm2) for 40 weeks. Photocarcinogenesis was retarded in terms of tumor incidence, and tumor latency, in mice deficient in TLR4 compared with TLR4-proficient mice, whereas significantly greater numbers of tumors occurred in TLR4-proficient mice. There was significant upregulation of inflammatory markers like COX-2, PGE2, S100A8, and S100A9 in the skin of TLR4-proficient mice than the skin of TLR4-deficient mice. Furthermore, we found that TLR4-proficient mice had a significantly higher number of Gr1+CD11b+ myeloid cells CD4+CD25+ regulatory T-cells than TLR4-deficient mice. Furthermore, the levels of interferon (IFN)-γ cytokine was increased and the levels of interleukin (IL)-4, IL-10, and IL-17 cytokines were decreased in serum, skin, and tumor lysates of TLR4-deficient mice in comparison with samples from TLR4-proficient mice. Together, our data indicate that TLR4-mediated inflammation may cause suppression of antitumor responses and trigger the development of UVB-induced skin cancers. Thus, strategies to inhibit TLR4-mediated immune suppression may allow us to develop preventive and therapeutic approaches for the management of UVB-induced cutaneous tumors.