Aim: To clarify the effectiveness and safety of x-ray-activated photodynamic therapy (X-PDT) for cutaneous squamous cell carcinoma (SCC) and melanoma. Materials & methods: Copper-cysteamine nanoparticles were used as a photosensitizer of X-PDT. The dark toxicity and cytotoxicity were studied in vitro. Tumor volume, microvessel density and acute toxicity of mice were evaluated in vivo . Results: Without x-ray irradiation, copper-cysteamine nanoparticles were nontoxic for keratinocyte cells. XL50 cells (SCC) were more sensitive to X-PDT than B16F10 cells (melanoma). X-PDT successfully inhibited the growth of SCC in vivo (p < 0.05), while the B16F10 melanoma was resistant. Microvessel density in SCC tissue was remarkably reduced (p < 0.05). No obvious acute toxicity reaction was observed. Conclusion: X-PDT is a safe and effective treatment for SCC.