In the presented studies, the effect of hydrogen ions on the stability of the tricyclic aciclovir derivative (i.e. 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-6-(4-methoxyphenyl)-9-oxo-5H-imidazo[1,2-a]purine; 6-(4-MeOPh)-TACV) and its esters (acetyl (Ac-), iso-butyryl (iBut-), pivaloyl (Piv-), ethoxycarbonyl (Etc-) and nicotinoyl (Nic-)) has been assessed. The HPLC chromatographic method (Lichrospher RP-18 column, 5 μm, 250 mm × 4 mm) with UV detection (262 nm) was used to observe changes in the concentration of the tested compounds. The mobile phase consisted of acetonitrile–phosphate buffer (pH 6; 20 mM; 17 mM KH2PO4, 3 mM K2HPO4) (35:65, v/v). The studies were carried out in the pH range 0.42–1.38 in the water-organic environment at constant ionic strength (0.50 M). The observed rate constants of the degradation reactions of the tested compounds were determined, kinetic equations describing the dependence of kpH as a function of pH for the proper acid catalysis were determined and the parameters of the equations describing the reaction of formation the observed product were determined. The dependence of durability on the chemical structure of the tested compounds was indicated and the mechanism of observed reactions was proposed.