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Crop residues contribute to the maintenance of soil organic carbon (SOC) stores, a key component of soil fertility and soil-based climate change mitigation strategies, such as the ‘4 per 1000’ initiative. Residues are also in demand in sectors coupled to crop production, such as the supply chain of livestock and bioenergy production. Ongoing debate revolves around balancing these competing uses, but science-based assessments of the long-term sustainability of residue exploitation are rare. This work uses biophysical simulation modelling to explore the likely response of SOC to different management strategies, using the land area of North Rhine-Westphalia (Germany) as a case study. Four strategies are tested: zero, one third and 100% removal of cereal residues, plus an approach proposed by the State farm advisory service. Simulations are carried out for the period 1971–2050 and 19 crop rotations coincident with land use throughout the study area. Uncertainty associated with the modelled SOC changes is explored by sampling values of relevant parameters for SOC turnover and running an ensemble of model configurations. Simulated SOC is used to trace time-dependent response functions following a change in residue management under different soil textures, initial SOC levels and crop rotations. Results highlight a general exponential decrease in SOC, with relative changes in 2050 distributed between +10% and −40% with respect to a reference period. SOC loss can be buffered or offset by returning all crop residues to the soil. Under such management, an SOC increase can be achieved on clayey soils characterized by a low initial SOC. Under moderate crop residue removal, positive SOC trends are limited to a few crop rotations. In this context, 4 per 1000 increase rate in SOC appears largely out of reach through residue management, calling for additional measures to meet the targets of land-based mitigation of anthropogenic emissions.