Protocatechuic acid (PA) is a natural phenolic compound which has been proven to have chemopreventive property against chemically induced carcinogenesis. The mixing enthalpies of PA with N-glycylglycine in sodium phosphate and potassium phosphate buffer solutions with different pH values have been investigated by mixing-flow isothermal microcalorimetry at T = 298.15 K. The heterotactic enthalpic interaction coefficients (h xy ) in the pH range of phosphate buffer solution from 3.0 to 8.0 have been calculated according to the McMillan−Mayer theory. Trends of the enthalpic pairwise interaction coefficients (h xy ) with increasing pH in both phosphate buffer solutions were obtained. The solvent and pH dependence of the h xy were discussed in terms of molecular interactions between solvated solute molecules.