Recently, we crossed an original haired RET-transgenic mouse of line 242 with a hairless mouse and established a hairless RET-(HL/RET)-transgenic mouse line (242-hr/hr) with hyperpigmented skin but no tumors. In this study, we examined the effect of hyperpigmented skin in HL/RET-transgenic mice on UV irradiation-mediated cutaneous cancer development. UV irradiation to this mouse line never induced melanoma despite the presence of melanoma-inducible transgenic RET oncogenes. On the contrary, the hyperpigmented skin efficiently protected UV-mediated squamous carcinoma development in the skin. Probably underlying this result, hyperpigmentation protected the skin from damage and blocked the accompanying signal transduction for tyrosine phosphorylation of multiple cellular proteins and activation/phosphorylation of extracellular signal-regulated, c-Jun N-terminal, and p38 kinases. Thus, we demonstrated hyperpigmentation-mediated in vivo protection against UV irradiation-induced skin cancer.