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It is known that microgravity and the reproduction of its effects in ground-based experimental models, for example, during "dry" immersion (DI), have a significant effect on the human cardiorespiratory system. The aim of the study was to experimentally determine the effect of 21-day DI on the reaction of the cardiorespiratory system to an increase of concentration of carbon dioxide (CO2) in the alveolar gas. Method. A study of the ventilation response of a person to hypercapnia under DI conditions was carried out in 10 subjects aged 24 to 32 years. During the experiment, the following was measured: 1) ventilation response to hypercapnia by the method of rebreathing into a hyperoxic gas mixture using the Hemosens software and hardware complex developed by us, 2) cerebral blood flow rate by rheoencephalography (REG), 3) lung volumes and transfer factor (KDLCO) by single inhalation method. Measurements were carried out once before the start of DI, on days 4, 8, 13, and 19 during DI, and once on day 4 after the end of DI. Results / Discussion. On the day 4 after DI, a significant (p <0.05 according to the parametric paired Student's t-test) increase by 25% in the ventilation response to carbon dioxide compared with period before the start of DI was observed. During the DI, the increase of the ventilation response grew, however, it was only the trend. The tidal volume response to CO2 was significantly higher on days 13 and 19 (p <0.05) of DI compared with response before the start of DI. Immediately after the start of the DI, all subjects had a decrease in FRC by about one liter. Further, the FRC remained at this level during the DI. KDLCO statistically significantly decreased during the entire 21-day DI in comparison with KDLCO before the DIand remained reduced on the day 4 after its end. According to the REG data, a decrease in the rate of cerebral volumetric blood flow during the DI was observed, compared with both "sitting" and "lying" positions, in period before the DI. Note that the increase in ventilation response to CO2 found here is comparable with the previously detected increase during the three-day DI [Dyachenko et al., 2015]. Conclusion. An increase in ventilation response to carbon dioxide was revealed during the 21-day DI, which persists and even becomes statistically significant on the day 4 after its end. At the same time, changes in the response of the tidal volume to CO2 during DI are more pronounced than the dynamics of ventilation response.