The hydrophobic component of complexation energy of double-stranded DNA with biologically active aromatic compounds was calculated using two semi-empirical methods-correlations of hydrophobic energy with changes of heat capacity (ΔCp) and solvent-accessible surface area (SASA). These surface areas were calculated for free ligands and DNA oligomers, unwound DNA duplexes and DNA-ligand complexes. The changes of polar and non-polar SASAs of molecules upon binding ligands to DNA were found. The hydrophobic contribution at both complexation stages was calculated. It was shown that the calculation of hydrophobic energy by SASA method is more correct than (ΔCp) method for DNA-binding ligands.