The origin of the vertical motions of East Greenland is a longstanding enigma. The area is characterized by a mountain chain >1000 km long, wherein the high peaks (2.5–3.7 km elevation) reside above a relatively thin crust (30–35 km). These mountains contain Mesozoic marine sediments uplifted to 1.2 km during the tectonic quietness of the middle to late Cenozoic. This uplifted area is cut by some of the world's biggest fjords. Scoresbysund fjord is as wide as 60 km, and cuts 400 km into the land and more than 4 km down from the peaks of the region. We test the potential amount of regional uplift and subsidence caused by the fjords' incision and associated deposition of sediments offshore. These tests are based on modeling the erosion process backward in time. The fjords are filled back to the summit surface while similar weights of sediments are removed from the shelf. The model considers the isostatic response of the lithosphere due to the loading and unloading of bedrock, sediments, water, and ice. Our estimates show that an average of almost 1.2 km of bedrock was eroded in the region from the middle Cenozoic summit surface. Most of the erosional products were deposited on the continental shelf outside the mouth of the fjords. Our calculations demonstrate that rocks in the central Fjord Mountains may be uplifted as much as 1.1 km due to the erosional unloading and flexural isostatic effects. Thus these effects should present a main part of the mechanisms responsible for the Cenozoic uplift in central East Greenland. Because the North Atlantic is rimmed by young glacially carved mountain chains, the model may be applicable to other parts of the area.