Background/Aims: CpG-oligodeoxynucleotides (ODNs) are synthetic DNA sequences containing unmethylated cytosine-guanine motifs with potent immunomodulatory effects. Previous reports showed a powerful protective effect of CpG-ODN against the damage induced by low-LET gamma-rays. In this study, we explored whether CpG-ODN also protects against the damage induced by high-LET irradiation. Parallel experiments were performed with low-LET irradiation. Methods: RAW264.7 cells were incubated with 1 mu M of CpG-ODN after gamma-ray or carbon-beam irradiation. Cell death was then measured by PI/DAPI double staining, cell survival was assessed by colony-formation assays, DNA damage was evaluated by comet assays, cell cycle was monitored by flow cytometry, and the levels of apoptosis-related proteins were detected by western blots. Results: When irradiated cells were treated with the CpG-ODN, cell viability decreased, cell survival increased, DNA damage and G(2)/M-phase arrest were ameliorated, and apoptosis was inhibited. Conclusions: The CpG-ODN showed protective effects against low-LET gamma-ray and high-LET carbon-beam irradiation. These effects might be associated with the repair of DNA damage and inhibition of apoptosis. Copyright (C) 2014 S. Karger AG, Basel