Melanoma cell lines that stably express green fluorescent protein (GFP) and nude mice that ubiquitously express red fluorescent protein (RFP) have previously been developed to study tumor-host interaction by color-coded imaging. In the present study, the efficacy of fluorescence-guided ultraviolet C (UVC) irradiation on the growth of murine melanoma expressing GFP in the ear of RFP mice was determined using a non-invasive ear-tumor imaging model developed previously. The GFP-expressing melanoma and RFP-expressing blood vessels from the transgenic mice expressing RFP used as hosts were readily visible using non-invasive imaging. The melanoma was treated under fluorescence guidance with UVC at 650 J/m2/minute for 3 minutes. The ears of the mice were observed before and 24 hours after irradiation with UVC. UVC inhibited melanoma growth and also damaged blood vessels in the tumor. Thus, UVC irradiation has a direct effect on melanoma growth as well as an anti-angiogenesis effect. This color-coded tumor-host model is useful for evaluation of treatment efficacy on melanoma growth and angiogenesis, which are readily discernable with non-invasive color-coded fluorescent protein imaging. These results suggest that fluorescence-guided UVC irradiation is a promising therapeutic strategy for melanoma.