Abstract. This paper quantifies and conditions expected hydrological responses in the Aral Sea Drainage Basin (ASDB; occupying 1.3% of the earth's land surface), Central Asia, to multi-model projections of climate change in the region from 20 general circulation models (GCMs). The aim is to investigate how uncertainties of future climate change interact with the effects of historic human re-distributions of water for land irrigation to influence future water fluxes and water resources. So far, historic irrigation changes have greatly amplified water losses by evapotranspiration (ET) in the ASDB, whereas 20th century climate change has not much affected the regional net water loss to the atmosphere. Results show that errors in temperature (T) and precipitation (P) from single GCMs have large influence on projected change trends (for the period 2010–2039) of river runoff (R), even though the ASDB is spatially well resolved by current GCMs. By contrast, observed biases in GCM ensemble mean results have relatively small influence on projected R change trends. Ensemble mean results show that projected future climate change will considerably increase the net water loss to the atmosphere. Furthermore, the ET response strength to any future T change will be further increased by maintained (or increased) irrigation practices, which shows how climate change and water use change can interact in modifying ET (and R). With maintained irrigation practices, R is likely to decrease to near-total depletion, with risk for cascading ecological regime shifts in aquatic ecosystems downstream of irrigated land areas. Without irrigation, the agricultural areas of the principal Syr Darya river basin could sustain a 50% higher T increase (of 2.3 °C instead of the projected 1.5 °C until 2010–2039) before yielding the same consumptive ET increase and associated R decrease as with the present irrigation practices.