Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA) is available for the treatment of actinic keratosis (AK). Recently, we developed a new PDT photosensitizer, ATX-S10(Na), and have shown that ATX-S10(Na) PDT is effective for the treatment of various human skin diseases, such as squamous cell carcinoma, Bowen's disease, basal cell carcinoma, and psoriasis. In the present study, we compared the effects of ATX-S10(Na) PDT and ALA PDT on hyperproliferative skin induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), on the squamous cell carcinoma cell line, SCC15, in vitro, and on UVB-induced skin tumors in vivo. TPA treatment induced epidermal acanthosis, which was more markedly suppressed by ATX-S10(Na) PDT than by ALA PDT. ATX-S10(Na) PDT more effectively eliminated UVB-induced AK and squamous cell carcinoma (SCC) than ALA PDT. Furthermore, both ATX-S10(Na) PDT and ALA PDT induced the death of SCC15 cells, and the effect of ATX-S10(Na) PDT was greater than that of ALA PDT. Our results indicate that ATX-S10(Na) PDT might be more effective than ALA PDT for the treatment of various skin diseases.