Heavy carbon-ion beam therapy has revealed several potential advantages over X-rays. Heavy-ion therapy has been applied for various solid tumors including esophageal squamous cell carcinoma (SCC). Although the local control rate of carbon ion radiotherapy for esophageal cancer has revealed better rates than that of conventional radiotherapy, some patients have shown resistance to the treatment. No study has evaluated whether anti-cancer drugs can enhance the anti-tumor effect of heavy carbon-ion beam irradiation. Therefore, we evaluated the efficacy of docetaxel, fluorouracil, cisplatinum, doxorubicin and gemcitabine to enhance the anti-tumor effects of heavy carbon-ion beam irradiation on human esophageal SCC cells in both in vitro and in vivo experiments. Fluorouracil, cisplatinum, doxorubicin and gemcitabine showed only additive anti-tumor effects. On the other hand, growth suppression was significantly potentiated by the combined treatment with heavy carbon-ion beam and docetaxel as compared to that treated with either agent alone. These data suggest that heavy carbon-ion beam irradiation combined with docetaxel may be a potentially useful therapeutic strategy for locally advanced esophageal SCC.