Binding of diclofenac sodium (DCF), a non-steroidal anti-inflammatory drug, to hexadecyltrimethylammonium bromide and tetradecyltrimethylammonium bromide micelles in water as well as in aqueous ethanol solutions (0.0, 1.0, 2.5, 5.0, 7.5, 10.0 %) has been studied using isothermal titration calorimetry (ITC), UV–visible spectroscopy, and dynamic light scattering (DLS) techniques. Calorimetric data indicate that DCF binds with both the surfactants in approx 1:1 stoichiometry with binding constant (Kb; obtained from ITC measurements) of order of 104 M−1. For both surfactants, Kb values increase and Gibbs free energy of binding (∆G0) decreases with ethanol concentration. Although ethanol weakens the hydrophobic interactions between two reacting species, the electrostatic interactions being stronger result in an overall increase in binding constant. Calorimetric results have been compared with those obtained spectroscopically. Further size variation studies on micelles upon binding with DCF (using DLS) complement the results obtained from these two techniques.