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Abstract: The issue of soil C sequestration is of special interest in Mediterranean areas, where, due to climatic conditions and agricultural practices, SOC (soil organic carbon) content is low, and is likely to be affected by climate change. Besides, losses of SOC have a relevant role in decreasing agricultural soil quality and could have a negative effect in productivity. Therefore, it is crucial to estimate whether modifying traditional soil management would have beneficial effects under future climate conditions. We used the EPIC model to simulate the interactive effect of climate change, CO2 enrichment, soil management (conventional tillage—CT vs. no tillage—NT) and two crop rotations, durum wheat–sunflower and durum wheat–maize, on crops yields and SOC in central Italy. The model was calibrated using soil and crop yield data collected from a long-term field experiment run in central Italy with CT and NT treatments. Maize and sunflower grain yields were significantly reduced by NT, primarily because of poor establishment, while durum wheat was almost not affected by tillage treatments. Projected durum wheat (Dw) and maize (Ma) grain yields were negatively affected by climate change (up to −25% and −10% respectively) while sunflower (Sf) yield increased. Tillage effects appear to be the most important factor in sequestering/releasing C. No-tillage practices sequestered in all profile (0–100cm depth) from 0.03 to 0.2tha−1 y−1 in 30 years, depending on climate scenario and plant C input, while conventional tillage (CT) led to massive C loss rates (up to −0.9tha−1 y−1). Beyond all uncertainties in the use of models, the results demonstrated that soil tillage and, to a certain extent, crop rotation, can play a relevant role in reducing (NT) or reinforcing (CT) the impact of climate change on SOC. No-tillage farming, if sufficient C input is ensured by the cropping system, could effectively contribute to increase soil C sequestration in Mediterranean rainfed environments. [Copyright &y& Elsevier]