The effects of ionic strength and temperature on the dissociation constants of adefovir (PMEA) and cidofovir (HPMPC) used as antiviral drugs were studied at 298 K, 308 K, and 318 K in aqueous media and at different ionic strength backgrounds of NaCl potentiometrically. The dissociation constants of the ligands were determined via the calculation of the titration data with the SUPERQUAD computer program. The thermodynamic parameters (Delta G, Delta H, and Delta S) for all species were calculated. The dissociation order of nitrogen and oxygen atoms in the ligands according to proton affinities values were obtained using PM6 semiempirical methods. Moreover, pK(a) values of the ligands were determined at 0.00, 0.10, 0.15, 0.20, and 0.5 mol dm(-3) ionic strength (NaCl) at 298 K. Consequently, when the ionic strength and temperature in the titration cells were increased, the obtained dissociation constants of PMEA (pK(a3), pK(a4), and pK(a5)) and HPMPC (pK(a2) and pK(a3)) decreased.