Initial land cover distribution varies among Earth system models, an uncertainty in initial conditions that can substantially affect carbon and climate projections. We use the integrated Earth System Model to show that a 3.9 M km 2 difference in 2005 global forest area (9-14% of total forest area) generates uncertainties in initial atmospheric CO 2 concentration, terrestrial carbon, and local temperature that propagate through a future simulation following the Representative Concentration Pathway 4.5. By 2095, the initial 6 ppmv uncertainty range increases to 9 ppmv and the initial 26 PgC uncertainty range in terrestrial carbon increases to 33 PgC. The initial uncertainty range in annual average local temperature of −0.74 to 0.96°C persists throughout the future simulation, with a seasonal maximum in Dec-Jan-Feb. These results highlight the importance of accurately characterizing historical land use and land cover to reduce overall initial condition uncertainty.Plain Language Summary International modeling efforts aim to understand global change and its impacts on humans and the environment. Modeling how human activities change vegetation (e.g., forest to cropland), and subsequently the greater environment, is difficult and highly uncertain, yet crucial to understanding impacts of global change. Here we estimate that an uncertainty range in year 2005 global forest cover of 3.9 M km 2 (9-14% of the total) generates an uncertainty of 6 ppmv in atmospheric carbon dioxide concentration that increases to 9 ppmv by 2095 in a model experiment that aims to restrict global warming forcing to 4.5 W/m 2 . Furthermore, local surface temperature uncertainties range from −0.57 to 0.72°C and persist throughout the 21 st century. Future studies of global change and its impacts on humans and the environment need to quantify and reduce such land cover uncertainties. A. (2020). Initial land use/cover distribution substantially affects global carbon and local temperature projections in the integrated earth system model. Global Biogeochemical Cycles, 34, e2019GB006383. https://doi.