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Using data from the Integrated Global Radiosonde Archive Version 2 (IGRA2) and the Multi Model Ensemble (MME) of four global climate models (GCMs), named CanESM5, IPSL-CM6A-LR, MIROC6, and MRI-ESM2-0, within the framework of phase 6 of the Coupled Model Intercomparison Project (CMIP6), we analyzed the changes in atmospheric total column water vapor (TCWV) over Central Asia in the future (2021–2100) under SSP-RCPs scenarios: SSP1-1.9, SSP1-2.6, SSP2-4.5, SSP3-7.0, SSP4-3.4, SSP4-6.0, and SSP5-8.5, relative to baseline period (1986–2005). Results showed that the annual mean TCWV from IGRA2 was consistent with the model output from 1979 to 2014 in Central Asia. Besides, the spatial distribution of TCWV in Central Asia during the baseline period was consistent between the models. The regional average value of Central Asia was between 10.8 mm and 12.4 mm, and decreased with elevation. TCWV will increase under different SSP-RCPs from 2021 to 2040, but showed different trends after 2040. It will increase under SSP1-1.9 and SSP1-2.6 scenarios from 2021 to 2050, and decrease after that. It will grow from 2021 to 2055 under SSP4-3.4 scenario, and then stay essentially constant. Under SSP2-4.5 and SSP4-6.0 scenarios, TCWV will rise rapidly during 2021–2065, but the growth will decline from 2065 to 2100. TCWV will continue to increase under SSP3-7.0 and SSP5-8.5 scenarios, and the largest increase is projected under SSP5-8.5 scenario. Change in near-surface temperature (Ts) matched the change in TCWV, but changes in precipitation and evapotranspiration are not significant during 2021–2100. In spite of the large variations in TCWV under different SSP-RCPs, the dominant characteristic in all scenarios shows that a large TCWV increase is demonstrated over areas with small TCWV amounts during the baseline period. On the contrary, increases will be small where the TCWV amounts had been large during the baseline period. The change in TCWV is highly correlated to the increase in Ts in Central Asia. Under SSP2-4.5, SSP3-7.0, SSP4-3.4, SSP4-6.0, and SSP5-8.5 scenarios, the higher the temperature due to higher radiative forcing, the steeper the regression slope between TCWV and Ts change. It is closest to the theoretical value of the Clausius-Clapeyron equation under SSP3-7.0 and SSP5-8.5 scenarios, but not presented under other scenarios. Spatially, steeper regression slopes during 2021–2100 have been found around the Caspian Sea in the southwest and in the high-elevation areas in the southeast of Central Asia, which is likely related to the abundant local water supply for evaporation. [ABSTRACT FROM AUTHOR]