High radon levels in the environment can lead to adverse biological effects such as DNA damage, thereby increasing cancer risk, especially lung cancer. This study focused on Tande-Tande sub-village in Mamuju, West Sulawesi, Indonesia, an area known for naturally high indoor radon concentrations, where inhabitants have been chronically exposed to radon throughout their lives. Blood samples from 38 subjects in Tande-Tande sub-village and the control area, Topoyo village, were examined. We then evaluated the DNA damage by assessing γ-H2AX for double-strand breaks and 8-hydroxydeoxyguanosine (8-OHdG) for oxidative damage. Additionally, we measured key molecules of the thioredoxin (Trx) system, Trx and thioredoxin reductase (TrxR), to gauge antioxidant levels and thus, oxidative stress response status. The C-reactive protein (CRP) to albumin ratio was analyzed to assess inflammatory status. Comparison of 8-OHdG, Trx, TrxR concentrations, and CRP/Albumin between the exposed and control groups were assessed by unpaired Student's t-test or Mann-Whitney test, depending on the normality of the data distribution. Correlations between concentration of 8-OHdG, Trx, TrxR or CRP/Albumin and indoor radon concentrations were investigated using either the Pearson or Spearman correlation tests, based on the distribution characteristics of the data. Our analyses of DNA damage markers (γ-H2AX and 8-OHdG), Trx, TrxR, and CRP/albumin ratio showed no significant increase in DNA damage markers in Tande-Tande sub-village residents compared to controls. Levels of 8-OHdG, Trx, and TrxR were significantly lower in Tande-Tande sub-village inhabitants when compared to the control area (P < 0.0001, P = 0.002, and P = 0.003, respectively), whereas CRP/albumin ratio did not differ significantly between these groups (P = 0.844). The present study did not find significant evidence of increased DNA damage, antioxidant system activity, or inflammatory status in inhabitants exposed to high radon levels. There is a possibility that the excessive ROS production existed in the early life period and subsequently manifested as a radio-adaptive response (RAR) during the adulthood of this population. These findings also support our previous assumptions that the excessive ROS production disrupts redox signaling and leads to a reduction in antioxidant levels. © 2025 by Radiation Research Society. All rights of reproduction in any form reserved.