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The primary and residual genome damage and its elimination rate were evaluated in peripheral blood lymphocytes of breast cancer patients treated with adjuvant radiotherapy after surgical removal of the tumor by mastectomy or quadrantectomy. The levels of DNA/chromosome damage were estimated before, throughout, as well as after six months, respectively one year after the radiotherapy, using the alkaline comet assay, the chromosome aberration analysis and the cytokinesis-block micronucleus assay. The marked individual differences in the baseline genome damage were observed in patients, which additionally increased until the end of the radiotherapy cycle. The levels of DNA/cytogenetic damage slowly declined during post-irradiation period; although in the majority of subjects they did not return to pre-therapy levels. In addition to the well-established comet parameters, the long-tailed nuclei were also proved as a useful indicator of individual DNA damage and response to radiation. One of the most important observation was that older breast cancer patients, irradiated after mastectomy, had higher values of almost all parameters evaluated. We found positive correlations between the comet assay parameters and the cytogenetic biomarkers that confirmed their complementary value in the assessment of the radiation sensitivity/susceptibility in elderly breast cancer patients. The specific patterns of DNA damage observed in the majority of subjects after a prolonged exposure to ionizing radiation indicate the possibility of adaptive response. Such results may also be linked to the hormesis theory and support previous observations, but the underlying mechanisms should be further investigated on a much larger population.