Mouse strains exhibit different susceptibilities to gamma-ray-induced thymic lymphomas. Our previous study identified Mtf-1 (metal responsive transcription factor-1) as a candidate susceptibility gene, which is involved in the radiation-induced signaling pathway that regulates the cellular reactive oxygen species (ROS). To reveal the mechanism for the increased susceptibility conferred by Mtf-1 locus, we examined early effects of gamma-ray on ROS levels in vivo and its difference between Mtf-1 susceptible and resistant congenic mice. Here, we show the detection of clonally growing thymocytes at 4 weeks after irradiation, indicating the start of clonal expansion at a very early stage. We also show that large thymocytes with higher ROS levels and a proliferation capacity were more numerous in the Mtf-1 susceptible mice than the resistant mice when examined at 7 days after irradiation, although such tendency was not found in mice lacking one allele of Bcl11b tumor suppressor gene. This high retention of the large thymocytes, at a high risk for ROS-induced mutation, is a compensatory proliferation and regeneration response to depletion of the thymocytes after irradiation and the response is likely to augment the development of prelymphoma cells leading to thymic lymphomas.