A selective difference spectrophotometric procedure is described for the assay of ethacrynic acid (a diuretic drug) in pharmaceutical dosage forms. The method is based on the reaction of the drug with N-acetylcysteine at pH 7.4 and ambient temperature, affording thiol adducts having different spectral properties, and involves the measurement of the absorbance of the reaction mixture relative to an equimolar solution of unreacted ethacrynic acid. The absorbance at 270 nm (A270) and the absorbance difference, ΔA=A270–A244, obtained from the difference spectrum, were found to be linearly correlated with the drug concentration. The proposed spectrophotometric procedure was applied successfully to the determination of ethacrynic acid in pharmaceutical formulations using a reversed-phase high-performance liquid chromatographic procedure as a reference method.