The extreme factors associated with space flight influence pronouncedly various physiological systems of the human body. The current study focuses on the impact of factors associated with prolonged space missions lasting up to 6 months on cellular innate immunity, hormonalregulation, and hemostasis in Russian cosmonauts. Immune system adaptation to the conditions of long-term space flight was shown to be accompanied by a significant increase in the level of monocytes and granulocytes, along with a decreased number of cells expressing adhesion molecules. The coagulation cascade, main anticoagulant and fibrinolysis proteins were also evaluated. The early post-flight period was characterized by elevated D-dimer levels compared to baseline values, indicative of blood clotting and fibrinolysis activation caused by a damage of endothelium during landing. aAlterations in blood rheology during re-adaptation to Earth conditions was also observed. The blood concentrations of aldosterone, cortisol, estradiol, testosterone, osteocalcin, and erythropoietin were analyzed, and their correlation with the parameters of hemostasis was assessed.The summary findings indicate an adaptive physiological reaction in cosmonauts associated with 6 months duration of spaceflight. The observations may be related to endothelium damage, which manifested in the activation of certain components of the immune system, along with the activation of fibrin clot formation and subsequent fibrinolysis.