This study provides the first accurate analysis of the energetics of solvation of blood porphyrins in binary solvents which are considered as appropriate models for a smooth transition from a polar protein-like phase to an apolar lipid-like environment. Our results do indicate that hematoporphyrin dimethylether dimethylester (HDEDE) and deuteroporphyrin dimethylether (DDE), as well as the model of their ester side-chains ethyl acetate (EtOAc), reveal more exothermic solvation in chloroform (CHCl3) than in dimethylformamide (DMF) and, especially, in 1-octanol (OctOH). The energetics of pair interaction between dissolved species and cosolvent molecules both in a protein-like and a lipid-like environment are clearly associated with these solvation effects. The interaction between blood porphyrins and DMF in OctOH is accompanied by large negative enthalpy changes at both temperatures, whereas in chloroform, forming strong H-bonds with dissolved species, the interaction is strongly thermochemically repulsive. All solute molecules interact in the energetically unfavorable way with OctOH and CHCl3 in DMF, the effect being much stronger pronounced for chloroform. The most significant result of this work is that it is possible to connect this pair interaction in a highly diluted solution with the solute behavior in the entire range of the binary mixture. The approach proposed is independent of a solute and solvent structure, it provides a good prediction of the energetics of solvation in mixed solvents and can be extended for a lot of other biologically active solutes. (C) 2014 Elsevier Ltd. All rights reserved.