Adaptive response (AR) and bystander effect are two important phenomena involved in biological responses to low doses of ionizing radiation (IR). Furthermore, there is a strong interest in better understanding the biological effects of high-LET radiation. In this study, we assessed in vitro the ability of priming low doses (0.01-0.1 Gy) of X-rays and heavy-ion radiation to induce an AR to a subsequent challenging dose (1-4 Gy) of high-LET IR (carbon-ion: 20 and 40 keV/µm, neon-ion: 150 keV/µm) in cultured lymphoblastoid TK6, AHH-1 and NH32 cells. Pre-exposure of p53-competent cells (both with low-dose X-rays and high-LET IR) resulted in decreased mutation frequencies at Hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus and different H2AX phosphorylation kinetics, as compared to cells exposed to challenging radiation alone. This phenomenon was independent of radiation-induced apoptosis or cell cycle effects. Taken together, our results suggested the existence of an AR to mutagenic effects of heavy-ion radiation in lymphoblastoid cells and the involvement of double-strand break repair mechanisms. Even though the cells directly hit by heavy-ion beams (even at low doses) are likely to suffer significant damage, our results constitute the first report to date indicating that low doses of high-LET radiation can nevertheless induce protective effects against subsequent high-LET irradiation. Taking inter-individual variability into account, these results might have interesting implications for high-LET radiation therapy and space research.