Binding of a positively charged indoloquinoline derivative to a G-quadruplex formed by the G-rich promoter element of the c-MYC oncogene was subjected to a rigorous isothermal calorimetric analysis. Binding of the indoloquinoline is primarily enthalpy-driven but is also promoted by a favorable entropy term. Both binding enthalpy Delta H degrees and binding entropy Delta S degrees exhibit a noticeable temperature dependence with almost complete enthalpyentropy compensation as a result of a negative change in heat capacity Delta C-p degrees. Salt-dependent polyelectrolyte effects only moderately contribute to the overall free energy of association. More details on the binding process are revealed in an attempt to dissect the total free energy into individual contributory terms. Accordingly, specific intermolecular interactions between the indoloquinoline ligand and G-quadruplex substantially contribute in addition to hydrophobic effects in promoting the association. Comparing thermodynamic profiles for various quadruplex ligands indicates different energetic patterns that may aid in the rational design of more efficient quadruplex binding ligands in the future.