To determine the long-term sensitivity of the Greenland ice sheet to a warmer climate, we explored how it responded to the Holocene thermal maximum (8–5 cal. kyr B.P.; calibrated to calendar years before present, i.e., A.D. 1950), when lake records show that local atmospheric temperatures in Greenland were 2–4 °C warmer than the present. Records from five new threshold lakes complemented with existing geological data from south of 70°N show that the ice margin was retracted behind its present-day extent in all sectors for a limited period between ca. 7 and 4 cal. kyr B.P. and in most sectors from ca. 1.5 to 1 cal. kyr B.P., in response to higher atmospheric and ocean temperatures. Ice sheet simulations constrained by observations show good correlation with the timing of minimum ice volume indicated by the threshold lake observations; the simulated volume reduction suggests a minimum contribution of 0.16 m sea-level equivalent from the entire Greenland ice sheet, with a centennial ice loss rate of as much as 100 Gt/yr for several millennia during the Holocene thermal maximum. Our results provide an estimate of the long-term rates of volume loss that can be expected in the future as regional air and ocean temperatures approach those reconstructed for the Holocene thermal maximum.