High-level ab initio and DFT methods up to MP2/6-311++G//B3LYP/6-31G and B3LYP/6-311++G//B3LYP/6-31G levels have been used to assess the relative energies of 17 different structures of D-glucose and 13 different structures of 4-deoxy-4-fluoro-D-glucose. The structures were confirmed to correspond to minima on the potential energy surface at the RHF/6-31G level. Solvation Model 5.4/AM1 was used to calculate the effects of aqueous solution. The substitution of a OH group by a F atom does not much change the shape and electrostatic potential around corresponding conformers, but in the gas phase it destabilizes the cooperative network of intramolecular hydrogen bonds. This destabilization mostly affects structures with a chain of intramolecular hydrogen bonds oriented counterclockwise, as fluorine is unable to donate a hydrogen bond and therefore causes a gap in the chain. In contrast, for clockwise-oriented networks of hydrogen bonds, the fluorine can act as an acceptor at the end of a chain of cooperative hydrogen bonds. A slightly higher energy of anomeric and exo-anomeric stabilization is another effect of substituting the fourth hydroxyl group by a fluorine atom in D-glucose, observed both in the gas phase and in aqueous solution. For this reason, the alpha anomers contribute more to the equilibrium population of structures of 4-deoxy-4-fluoro-D-glucose than D-glucose. In aqueous solution, both D-glucose and its 4-deoxy-4-fluoro analogue are present as a mixture of mainly three corresponding structures. This indicates that 4-deoxy-4-fluoro-D-glucose is a good substitute for D-glucose in terms of its biochemical and biological activity. Moreover, this suggests that, for molecules with limited conformational freedom, the substitution of a OH group by a F atom is very likely to lead to a potential new drug. In contrast, it had already been shown that, for conformationally labile aliphatic compounds, replacement of a hydroxyl by a fluorine increases conformational diversity, so the fluorine-containing aliphatic molecules were not likely to be an example of a successful drug design. On the other hand, this work shows that, among molecules with limited conformational freedom, such as cyclic compounds, one is very likely to find targets for a successful rational drug design.