In the present work the origin of highly varied acidity of hydroxycoumarins (pK(a) values) has been for the first time investigated by joint experimental and computational studies. The structurally simple regio-isomers differing in the location of hydroxyl group, 3-hydroxycoumarin (3-HC), 4-hydroxycoumarin (4-HC), 6-hydroxycoumarin (6-HC), 7-hydroxycoumarin (7 -HC), as well as 4,7-dihydroxycoumarin (4,7-HC) and the larger 4-hydroxycoumarin-based derivatives: warfarin (WAR), 7-hydroxywarfarin (W7), coumatetralyl (CT), and 10-hydroxywarfarin (W10), have been compared in terms of enthalpy-entropy relationships accounting for the observed pK(a), values. We have revealed that in the case of large molecules the acidic proton is stabilized by the following noncovalent interactions OH center dot center dot center dot O (WAR and W7), OH center dot center dot center dot pi (CT), and OH center dot center dot center dot OH center dot center dot center dot O (W10), this effect leads to a compensatory enthalpy-entropy relation and yields a moderate pKa increase. On the other hand, different location of the hydroxyl group in the regio-isomers (3 -HC, 4 -HC, 6 -HC, and 7 -HC) leads to the massive changes in acidity due to a lack of enthalpy-entropy compensation. Our results suggest that the solvent-solute interactions and electron delocalization degree in anions contribute to the observed behaviors. Such knowledge can be useful in the future to design novel systems exhibiting desired acid-base properties, and to elucidate enthalpy-entropy compensation phenomena.