During the Last Interglacial (LIG, ~130–115 kiloyears (kyr) before present (BP)), the northern high latitudes were characterized by higher temperatures than those of the late Holocene and a lower Greenland Ice Sheet (GIS). However, the impact of a reduced GIS on the global climate has not yet been well constrained. In this study, we quantify the contribution of the GIS to LIG warmth by performing various sensitivity studies based on equilibrium simulations, employing the Community Earth System Models (COSMOS), with a focus on height and extent of the GIS. We present the first study on the effects of a reduction in the GIS on the surface temperature (TS) on a global scale and separate the contribution of astronomical forcing and changes in GIS to LIG warmth. The strong Northern Hemisphere summer warming of approximately 2°C (with respect to preindustrial) is mainly caused by increased summer insolation. Reducing the height by ~1300m and the extent of the GIS does not have a strong influence during summer, leading to an additional global warming of only +0.24°C compared to the purely insolation-driven LIG. The effect of a reduction in the GIS is, however, strongest during local winter, with up to +5°C regional warming and with an increase in global average temperature of +0.48°C. In order to evaluate the performance of our LIG simulations, we additionally compare the simulated TS anomalies with marine and terrestrial proxy-based LIG temperature anomalies derived from three different proxy data compilations. Our model results are in good agreement with proxy records with respect to the warming pattern but underestimate the magnitude of temperature change when compared to reconstructions, suggesting a potential misinterpretation of the proxy records or deficits in our model. However, we are able to partly reduce the mismatch between model and data by additionally taking into account the potential seasonal bias of the proxy record and/or the uncertainties in the dating of the proxy records for the LIG thermal maximum. The seasonal bias and the uncertainty of the timing are estimated from new transient model simulations covering the whole LIG. The model–data comparison improves for proxies that represent annual mean temperatures when the GIS is reduced and when we take the local thermal maximum during the LIG (130–120 kyr BP) into account. For proxy data that represent summer temperatures, changes in the GIS are of minor importance for sea surface temperatures. However, the annual mean and summer temperature change over Greenland in the reduced GIS simulations seems to be overestimated as compared to the local ice core data, which could be related to the interpretation of the recorder system and/or the assumptions of GIS reduction. Thus, the question regarding the real size of the GIS during the LIG has yet to be answered.