Abstract <p>The complex of extreme factors of space flight induces various changes in the cardiovascular system at the structural and functional level. The study of protein markers by proteomics methods, included in the compensation of dysfunctional disorders of the cardiovascular system in long-term space flights, is relevant. The aim of the work: search for the main proteomic markers in dry spots of blood, included in the adaptation of the cardiovascular system during long-term space flights. To analyze the content of peptides in dry spot extracts, targeted liquid chromatograph mass spectrometric analysis with multiple reaction monitoring (LC-MRM MS) was used, using synthetic internal standards (SLSs). As a result of statistical and bioinformatics analysis, using ANDvisio software, it was established that the content of proteins involved in the adaptation of the cardiovascular system in dried blood spot extracts changed significantly during space flight: on the 7th day—11 proteins, after 3 months—Q5 proteins, and after 6 months—3 proteins. The main biological functions of these proteins are described, as applied to the duration of space flight and their participation in the adaptation of the cardiovascular system to a complex of extreme factors, including endothelial regeneration, angiogenesis, and processes aimed at restoring the elasticity and contractility of vascular smooth muscle cells. Proteins involved in the control of cellular oxidative stress are expressed at all points in the study. The data obtained are of practical importance in relation to the assessment of the risks of cardiovascular events during long-term space flights.</p>