In order to investigate the impact of spatial resolution on the discrepancy between simulated δ18O and observed δ18O in Greenland ice cores, regional climate simulations are performed with the isotope-enabled regional climate model (RCM) COSMO_iso. For this purpose, isotope-enabled general circulation model (GCM) simulations with the ECHAM5-wiso general circulation model (GCM) under present-day conditions and the MPI-ESM-wiso GCM under mid-Holocene conditions are dynamically downscaled with COSMO_iso for the Arctic region. The capability of COSMO_iso to reproduce observed isotopic ratios in Greenland ice cores for these two periods is investigated by comparing the simulation results to measured δ18O ratios from snow pit samples, Global Network of Isotopes in Precipitation (GNIP) stations and ice cores. To our knowledge, this is the first time that a mid-Holocene isotope-enabled RCM simulation is performed for the Arctic region. Under present-day conditions, a dynamical downscaling of ECHAM5-wiso (1.1◦ × 1.1◦) with COSMO_iso to a spatial resolution of 50km improves the agreement with the measured δ18O ratios for 14 of 19 observational data sets. A further increase in the spatial resolution to 7km does not yield substantial improvements except for the coastal areas with its complex terrain. For the mid-Holocene, a fully coupled MPI-ESM-wiso time slice simulation is downscaled with COSMO_iso to a spatial resolution of 50km. In the mid-Holocene, MPI-ESM-wiso already agrees well with observations in Greenland and a downscaling with COSMO_iso does not further improve the model–data agreement. Despite this lack of improvement in model biases, the study shows that in both periods, observed δ18O values at measurement sites constitute isotope ratios which are mainly within the subgrid-scale variability of the global ECHAM5-wiso and MPI-ESM-wiso simulation results. The correct δ18O ratios are consequently not resolved in the GCM simulation results and need to be extracted by a refinement with an RCM. In this context, the RCM simulations provide a spatial δ18O distribution by which the effects of local uncertainties can be taken into account in the comparison between point measurements and model outputs. Thus, an isotope-enabled GCM–RCM model chain with realistically implemented fractionating processes constitutes a useful supplement to reconstruct regional paleo-climate conditions during the mid-Holocene in Greenland. Such model chains might also be applied to reveal the full potential of GCMs in other regions and climate periods, in which large deviations relative to observed isotope ratios are simulated.