Mannitol and sorbitol are steriosomers that differ only in the position of one of their six hydroxy groups. In aqueous solution the properties of both are quite different, and it is generally assumed that the differences are due to specific interactions with water. In order to study the effect of solvent on the conformation of sorbitol and mannitol, a simulation by molecular dynamics of both polyalcohols, in vacuo and in water was made. Mannitol was also simulated in an argon-like Lennard-Jones solvent. Simulation in vacuo showed that both polyols are bent, while in water it becomes clear that mannitol adopts a planar zig-zag configuration and sorbitol is bent. The resulting end-to-end distances are 0.635 nm for mannitol and 0.547 nm for sorbitol, with a radius of gyration of 0.417 and 0.372 nm, respectively. When mannitol is simulated in a Lennard-Jones solvent, starting from the extended configuration, it is observed that it quickly bends. It is concluded that the assumption that the configurations of sorbitol and mannitol are determined by solute–solvent interactions is well justified. From an analysis of water residence times a negative hydration is observed in both polyalcohols.