The ability of the Conductor-like Screening Model for Realistic Solvation (COSMO-RS) computational method to model hydrogen bond (HB) formation in solution is examined by comparing computational data with experimental data from literature. This is the first study of this kind where mixed solvents are also involved. Hydrogen bond formation is examined between neutral molecules, between acids and their anions, and between various anion receptor molecules and different anions in a number of aprotic solvents. HB formation equilibrium constants, the corresponding Gibbs’ free energies and, when available from the literature, enthalpies were calculated. The supermolecule (SM) approach and the contact probability (CP) approach were used. Both in the case of the SM and CP approach, good to very good correlations between the experiment and computations are found for complexes formed from neutral species, enabling quantitative predictions. When the HB acceptor is an anion, the correlations are poor and in some cases even qualitative predictions fail.