The interactions of amphiphilic drug(propranolol hydrochloride, PPL) with cationic surfactants, such as dodecyltrimethylammoniumbromide(DTAB), tetradecyltrimethylammonium bromide (TTAB), trimethyltetradecylammonium chloride(TTAC) and tetyltrimethylammonium bromide(CTAB), in an aqueous medium were evaluated. The surface tension measurement was used to examine the mixed micellization behavior and surface properties of drug-surfactant mixtures. The nonideal or synergistic behaviors of the mixed systems were explored by using several physical models, such as Clint, Rubingh, Rosen, and Motomura models, based on regular solution theory and pseudophase approximation. In addition, the synergism between PPL and cationic surfactants was also confirmed using ultraviolet-visible spectroscopy. The stoichiometric ratios, binding constants, and free energy changes of the drug-surfactant mixtures were computed using Benesi-Hildebrand (B-H) theory.