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Variable-Resolution Community Earth System Model (VR-CESM) employs a global grid which is refined only over a limited area, thus substantially decreasing the computational demand while allowing global simulations with regional resolutions that are mostly unaffordable with uniform resolution GCMs. This technique can leverage today’s parallel computing platforms almost to their fullest extent by offering near-perfect scalability. The geographic location and complicated topography of Euro-Mediterranean leads to a regional climate governed by complex nonlinear interactions and cascade of feedbacks between multitude of scales, from global to local, and spatiotemporally highly varied climatic characteristics. Therefore, the region serves as a suitable testbed for the utilization of VR-CESM.Here, VR-CESM is employed to investigate the climate of the Euro-Mediterranean region. Two variable-resolution grids with regionally refined resolutions of 0.25° and 0.125° over the study domain are used and historical climate is simulated for between 1998-2014 in an Atmospheric Model Intercomparison Project (AMIP) setup. The fidelity of VR-CESM simulations is evaluated considering the near-surface air temperature and precipitation fields in comparison to available observation-based data sets and those of a coarse resolution (quasi-uniform 1°) control simulation.The improvements obtained are mainly related to a better representation of the complex topography of the region with higher resolution and consistent incorporation of the large scale circulation. Specifically, we report improvements in the representation of the topographically induced processes (e.g. orographic uplift), extreme events, vertical air motion and synoptic scale moisture transport. Overall, this work validates the benefits of VR-CESM for use in regions under the influence of many processes across global-to-regional scales coupled with a complex topography and that, as a modeling approach, VR-CESM is a useful (even superior for some scientific inquiries) alternative to investigate the Euro-Mediterranean’s climate.