In this study, human-induced climate change over the Eastern Mediterranean–Black Sea region has been analyzed for the twenty-first century by performing regional climate model simulations forced with large-scale fields from three different global circulation models (GCMs). Climate projections have been produced with Special Report on Emissions Scenarios A2, A1FI and B1 scenarios, which provide greater diversity in climate information for future period. The gradual increases for temperature are widely apparent during the twenty-first century for each scenario simulation, but ECHAM5-driven simulation generally has a weaker signal for all seasons compared to CCSM3 simulations except for the Fertile Crescent. The contrast in future temperature change between the winter and summer seasons is very strong for CCSM3-A2-driven and HadCM3-A2-driven simulations over Carpathians and Balkans, 4–5 °C. In addition, winter runoff over mountainous region of Turkey, which feeds many river systems including the Euphrates and Tigris, increases in second half of the century since the snowmelt process accelerates where the elevation is higher than 1,500 m. Moreover, analysis of daily temperature outputs reveals that the gradual decrease in daily minimum temperature variability for January during the twenty-first century is apparent over Carpathians and Balkans. Analysis of daily precipitation extremes shows that positive trend is clear during the last two decades of the twenty-first century over Carpathians for both CCSM3-driven and ECHAM5-driven simulations. Multiple-GCM driven regional climate simulations contribute to the quantification of the range of climate change over a region by performing detailed comparisons between the simulations.