Binding enthalpies (Delta H), entropies (Delta S) and free energies (Delta G) have been evaluated for complex formation of tetracycline with Mg2+, Mn2+, Ca2+, and Sr2+. From the temperature dependence of enthalpic and entropic components, the changes in heat capacities (Delta C-p) accompanying complex formation have been determined. The magnitudes of these thermodynamic parameters show a strong correlation with the charge-density of the metal ion, and reflect changes in the immediate hydration sphere of the metal-drug complex that are likely to be involved in defining the extent of any interactions with nucleic acids. The similar binding constants exhibited by the physiologically relevant Mg2+ and Ca2+ ions do not reflect the variation in entropic and enthalpic factors that underlie complex formation for each of these metal ions.