In this study, projected changes in the future climate conditions for the Middle East-North Africa domain over the 21st century have been investigated. Two simulations with the COSMO-CLM model have been conducted respectively, at a spatial resolution of 0.44° and 0.22°, over the period 1979–2100, employing the IPCC RCP4.5 scenario. Initial and boundary conditions have been derived by the global model CMCC-CM. The main aim of the work is to provide regional climate projections for this area, widening the range of the data already available, yet with higher resolution, useful for many applications, especially as an input for the impact models. The two different resolutions have been employed in order to quantify the differences due to the spatial scale effects, comparing the results also with the driving global model. Climate projections show a significant warming expected over the whole area considered at the end of the 21st century, along with a reduction in precipitation, which is particularly evident over the western part of the domain. Precipitation projections depend on the horizontal resolution, suggesting the need for additional simulations at higher resolution, especially for a proper representation of extreme weather events.