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Long-term soil carbon (C) dynamics in agro-ecosystems is controlled by interactions of climate, soil and agronomic management. A modeling approach is a useful tool to understand the interactions, especially over long climatic sequences. In this paper, we examine the performance of the Agricultural Production Systems sIMulator (APSIM) to predict the long-term soil C dynamics under various agricultural practices at four semi-arid sites across the wheat-belt of eastern Australia. We further assessed the underlying factors that regulate soil C dynamics in the top 30 cm of soil through scenario analysis using the validated model. The results show that APSIM is able to predict aboveground biomass production and soil C dynamics at the study sites. Scenario analyses indicate that nitrogen (N) fertilization combined with residue retention (SR) has the potential to significantly slow or reverse the loss of C from agricultural soils. Optimal N fertilization (N-opt) and 100% SR, increased soil C by 13%, 46% and 45% at Warra, Wagga Wagga and Tarelee, respectively. Continuous lucerne pasture was the most efficient strategy to accumulate soil C, resulting in increases of 49%, 57% and 50% at Warra, Wagga Wagga and Tarlee, respectively. In contrast, soil C decreases regardless of agricultural practices as a result of cultivation of natural soils at the Brigalow site. Soil C input, proportional to the amount of retained residue, is a significant predictor of soil C change. At each site, water and nitrogen availability and their interaction, explain more than 59% of the variation in soil C. Across the four sites, mean air temperature has significant (P < 0.05) effects on soil C change. There was greater soil C loss at sites with higher temperature. Our simulations suggest that detailed information on agricultural practices, land use history and local environmental conditions must be explicitly specified to be able to make plausible predictions of the soil C balance in agro-ecosystems at different agro-ecological scales. Crown Copyright (C) 2011 Published by Elsevier B.V. All rights reserved.