Abstract: The orthogonal function spectrophotometric method was successfully applied to the direct determination of sulfamethazine in combination with sulfaguanidine and of diphenhydramine-HCl without separation of ephedrine-HCl. In 0.1 N HCl, use of the 6-point quadratic polynomial the wavelength range 242 to 302 nm at 12 nm intervals, the coefficient of the polynomial, P₂, provides a precise estimate for sulfamethazine and eliminates the interference from sulfaguanidine. In 0.1 N sulfuric acid, the wavelength range 239 to 249 nm at 2 nm intervals and using 6-point quadratic orthogonal polynomial to calculate d₂, the unnormalized coefficient, d₂ was found to be independent of the content of ephedrine-HCl. The unnormalized coefficient, d_w=2d₂-d₃ of the combined polynomial, calculated between wavelength range 240.5 to 255.5 nm at 3 nm intervals was also independent of the content of ephedrineHCl. The normalized factors of N₂ and N₃ can be omitted for simplifying the calculation. The proposed method is simple and the results obtained by this method are satisfactory both in accuracy and in precision.