The five-year experience of experimentation in the autonomic regulation of blood circulation on board the International Space Station is presented. The heart rate variability (HRV) analysis was the basic methodical approach in these investigations. The probabilistic approach to the estimation of the risk of pathology under long-term spaceflight conditions based on HRV analysis is described. The individual type of autonomic regulation was taken into account in the analysis of the results of the investigations. The type of regulation inherent in every cosmonaut under the conditions of weightlessness has been shown to be retained during subsequent flights. New scientific data on the relationship between the character of the adaptive response of the body to spaceflight factors and the individual type of autonomic response have been obtained. Staying in weightlessness has been shown to be connected with the readjustment of regulatory systems and with transition to the zone of prenosological states. Adaptation responses in weightlessness are characterized by the increased tension of the regulatory systems and the preservation of sufficient functional reserves. The mobilization of additional resources is required after returning to earth, due to which the functional reserve of the mechanisms of regulation decreases. Cosmonauts with the vagotonic and normosympathotonic types of autonomic regulation appear to be the most resistant. The knowledge of the type of autonomic regulation allows us to judge the potential response of the cosmonaut to spaceflight factors. The likelihood estimates were calculated, and the risk categories were determined by the results of HRV analysis in the last months of the flight. Three pathology risk groups were identified. In conclusion, the theoretical and applied significance of the experiments was considered.