We performed the first ever comparative analysis of modifications in the proteome, ionogram and some other blood plasma biochemical indices of 18 male cosmonauts (44 ± 6 years of age) before and after maiden or repeated long-term missions to the Russian segment of the International space station (ISS RS). Levels of proteins, substrates and ions as well as chemical components were measured using the LC-MS-based proteomics and routine biochemical techniques. A total of 256 to 281 indices were investigated with the methods of descriptive statistic, regression analysis, and access to bioinformatics resources. It was shown that blood indices recovery from the maiden and repeated missions reflects changes in the body systems and goes at a various speed. The results of measurements made prior to launch and on day 7 after landing are dependent on the number of missions. The bioinformatics techniques showed that after maiden missions both the mediator proteins of alkaline phosphatase (AP) and blood proteins with reliably changing concentrations are associated with the bio-processes including stress, metabolism and DNA reparation, apoptosis, catabolism and proteolysis. During early re-adaptation from repeated missions the AP level was affected by bone remodeling, phosphorylation, angiogenesis and coagulation cascade suggesting a distinct and urgent trigger of the processes of bone structure and mineralization.