Abstract：As a high linear energy transfer (LET) radiation, ?琢 particles mainly induce DNA clustered damage with low repair efficiency and serious biological effects. There is still no effective radioprotection agent available against the biological detriments induced by ?琢 particles. The vanillin derivative VND3207 is a novel radioprotection agent with an antioxidant potentiality and protective effects against the genomic DNA damage and apoptosis induced by low LET γ-ray. The present study is designed to determine the radioprotective effect of VND3207 against the genomic DNA damage of human fibroblast HFS cells induced by high LET α particles. The clonogenic survival assay shows that VND3207 can significantly enhance radioresistance of HFS cells to the irradiation of α particles, no matter the cells are treated with VND3207 before or after irradiation. Multiple indicators of DNA damage detection, including single cell gel electrophoresis, immnuo-fluorescent γ-H2AX foci, γ-H2AX protein expression and micronuclei assay, demonstrate that VND3207 can effectively decrease the initial DNA double-strand break level as well as increase the cellular DNA repair capacity and reduce the residual damage level. The effective concentration is as low as 10~20 mol/L. In conclusion, VND3207 has radioprotective effects on cell survival and genomic stability against the irradiation of α particles, and it is of value to develop radioprotective drugs against high LET radiation.