In this work, a new simple spectrophotometric method is presented for determination of the two antihypertensive binary mixtures of hydrochlorothiazide (HCT) with either carvedilol (CRV) or losartan potassium (LOS) without prior separation. The proposed method is based on generation of ratio spectra of one compound using the other as a divisor followed by measurement of the ratio-difference (peak-to-trough) amplitudes between two selected wavelengths in the ratio spectra. For analysis of HCT/CRV mixture, 20 μg/mL CRV was used as a divisor, and the ratio-difference amplitudes between 287 and 299 nm were plotted against HCT concentration. Similarly, by using 20 μg/mL HCT as a divisor, the peak-to-trough amplitudes between 269.5 and 287.5 nm were found proportional to CRV concentration. Calibration curves were linear in the range 5 - 80 μg/mL for both drugs. For determination of HCT/LOS mixture, a standard solution of LOS 50 μg/mL was used as a divisor, and the ratio-difference amplitudes between 224 and 275 nm were measured and correlated to HCT concentration. Similarly, HCT 50 μg/mL was set as a divisor in LOS determination and the peak-to-trough amplitudes between 242 and 275 nm were recorded. Calibration curves were linear over the concentration ranges 5-50 and 5-60 μg/mL for HCT and LOS, respectively. The developed methods were validated following the ICH guidelines and successfully applied to the determination of the studied drugs in various laboratory prepared mixtures. In addition, satisfactory results were obtained from analysis of the tablets dosage forms with no significant statistical differences from the reference methods.