The geometry of the ice sheets during the Pliocene to early Pleistocene is not well constrained. Here we apply an ice-flow model in the study of the Greenland ice sheet (GIS) during three extreme intervals of this period constrained by geological observations and climate reconstructions. We study the extent of the GIS during the Mid-Pliocene Warmth (3.3–3.0 Ma), its advance across the continental shelf during the late Pliocene to early Pleistocene glaciations (3.0–2.4 Ma) as implied by offshore geological studies, and the transition from glacial to interglacial conditions around 2.4 Ma as deduced from the deposits of the Kap København Formation, North Greenland. Our experiments show that no coherent ice sheet is likely to have existed in Greenland during the Mid-Pliocene Warmth and that only local ice caps may have been present in the coastal mountains of East Greenland. Our results illustrate the variability of the GIS during the Pliocene to early Pleistocene and underline the importance of including independent estimates of the GIS in studies of climate during this period. We conclude that the GIS did not exist throughout the Pliocene to early Pleistocene, and that it melted during interglacials even during the late Pliocene climate deterioration.