Extracellular DNA of blood plasma (cell-free DNA, cfDNA) may potentially indicate a total level of apoptosis and mediate the immune response to stress induced by extreme environmental conditions, such as Antarctic wintering. We studied blood nuclease activity (NA); the content of 8-oxodG, rDNA, and SatIII(1q12) in cfDNA; and the levels of BAX, BCL2, TLR9, AIM2, STING, RIG-I, NF-kB, IL-8, and IL-17A mRNAs in 11 males, the members of the 64th Russian Antarctic Expedition. Blood was sampled before the wintering and on the 27th, 85th, 160th, 270th, and 315th days. The early months of the wintering are characterized by increased rates of apoptosis, an elevated BAX/BCL2 RNA ratio in blood leukocytes, and high cfDNA concentrations and NA in blood plasma. The properties of cfDNA are dramatically changed: the content of GC-rich rDNA rises, while AT-rich SatIII and 8-oxodG are low. We note individual multidirectional changes in the expression of TLR9 and AIM2, while STING and RIG-I are downregulated in all of the subjects. The mRNA levels of NFKB1, IL-8, and IL-17A increase dramatically, indicating immune system activation. In conclusion, (1) apoptosis is overactivated and remains elevated during the first half of the Antarctic wintering; (2) cfDNA is enriched with GC-repeats, which stimulates its biological activity; and (3) the expression of immunity genes associated with the inflammatory response is increased. © 2025 Elsevier B.V., All rights reserved.