We report for the first time the effect of liophilic mobile phase additives on the mechanism of chiral recognition of basic chiral pharmaceutical on a vancomycin based chiral stationary phase (CSP). Using methanol as the mobile phase and 0.005% formic acid as pH modifier, we evaluated the effect of different concentrations of three types of liophilic anions, formate (HCOO−), nitrate (NO3−), and acetate (CH3COO−), on enantioresolution (Rs), enantioselectivity (α) and retention factor (k) of enantiomers of fluoxetine and atenolol. The effect of liophilic ion types on k followed the Hofmeister series: CH3COO− > HCOO− > NO3−. Increasing concentration from 4 to 20 mM resulted in decreases in Rs and k in accordance to hydrophobicity of the liophilic anion. The effect of temperature or mobile phase composition on enantioseparation was determined at 13–40 °C. For both analytes, standard changes in enthalpy (ΔH°) and entropy (ΔS°) calculated using van’t Hoff plots (ln k against 1/T) to varied from −4.99 to −0.63 kJ/mol and −11.82 to 9.47 J/mol, respectively. The van’t Hoff plots showed elution order of the enantiomers of each analyte did not reverse in the temperature range studied. Chiral recognition of the enantiomers of atenolol and fluoxetine in the presence of liophilic ions was enthalpy driven.