Modeling the relative reactivity of the hydroxy functions of carbohydrates may be of interest to understand and predict selective synthesis. In the present work, the chemical reactivity of sucrose has been evaluated using semiempirical molecular orbital (AM1 and PM3) frameworks. A simple conformational equilibrium of sucrose consistent with NMR experiments was taken into account. The Potential Electrostatic Surface computed from partial atomic charges failed to provide useful information, in part because of the multiconformational problem. Semiempirical calculations of deprotonation enthalpies (DPEs) could provide a comparative scale for acidity of the various hydroxyl groups. DPE averaging showed that the O-2g hydroxy function is by far the most acidic position of the molecule. These results, which are in good agreement with experimental chemical observations, indicate that intramolecular hydrogen bonds also play a key role on the acidity of the sucrose hydroxyls. The order of acidity of the various hydroxyl groups is O-2g"H-2g≫O-3g"H-3g>O-3f"H-3f>O-1f"H-1f=O-4g"H-4g>O-4f"H-4f≫O-6g"H-6g≫O-6f"H-6f. Despite these encouraging results it should be stressed that the application of such modeling techniques is not yet straightforward, and that the enhanced conformational flexibility of sucrose, including the secondary hydroxyl groups orientation, is still a limiting factor in a complete unravelling of the chemical reactivity of this carbohydrate molecule.