Difference spectrophotometry, based on the utilization of difference absorption spectra corresponding to the same compound obtained at two different pH's, has been investigated for the analysis of binary mixtures. The method has been applied to the simultaneous determination of bromophenol blue and methyl orange, and two different binary mixtures of sulfonamides i.e., sulfamethoxazole (SX)-sulfaquinoxaline (SQ) and sulfathiazole (ST)-sulfamethoxazole (SX). In addition, the determination of SX, SQ and ST in the presence of sulfanilamide (SB) has been performed. For the determination of ST and SX, first-derivative difference spectrophotometry was applied. A comparative study of the advantages of the pH-induced difference method with respect to first-derivative spectrophotometry is presented.