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In the present study, we report on the interaction between an antidepressant drug, amitriptyline hydrochloride, and nonionic surfactants (t-octylphenoxypolyethoxyethanol (TX-100), polyethoxyglycol t-octylphenyl ether (TX-114)), in aqueous electrolyte solutions, with special attention paid to the possible contribution from the ion–dipole type of interaction, by using a spectroscopic approach. The structural difference in the drug and nonionic surfactants also plays a role in tuning the aggregational behavior of the drug–surfactant mixtures. From the I 1/I 3 versus total surfactant concentration plots, the mixed critical micelle concentration (cmc) of various mixtures was computed. Critical assessments by applying Clint, Rubingh, and Motomura models confirm strong interactions in mixed micelle in the bulk of aqueous electrolytic solution. The various micellar parameters, such as micelle mole fraction (), interaction parameter (βm), micropolarity, and micelle aggregation number (N agg), have been determined for all different ratio mixtures. Micelle aggregation numbers (N agg) indicate that the contribution of nonionic surfactants was always more than that of the drug. Stern–Volmer binding constants (K sv) and dielectric constant of mixed systems have also been evaluated from the ratios of respective peak intensities (I 1/I 3 or I 0/I 1).