The interactions of cationic amphiphilic drugs (CADs) imipramine hydrochloride (IMP) and promethazine hydrochloride (PMT) with nonionic polyoxyethylenes (Brij 35, 56, 58) have been investigated using tensiometry at four different temperatures ranging from 288.15 to 303.15K. Despite the attractive interactions (of ion–dipole type) between cationic amphiphilic drugs and nonionic surfactants there occurs an increase in values of A_min in the mixed monolayer. Steric factor appears to play an important role during interaction when surfactant molecular structure varies in size of the headgroup. The temperature has been observed to be vital in controlling the dehydration and thermal agitation which, in turn, makes an environment conducive for aggregational behavior of the drug–surfactant mixtures in aqueous solution.