Abstract: A new simple spectrophotometric method was developed for the determination of binary mixtures without prior separation. The method is based on the generation of ratio spectra of compound X by using a standard spectrum of compound Y as a divisor. The peak to trough amplitudes between two selected wavelengths in the ratio spectra are proportional to concentration of X without interference from Y. The method was demonstrated by determination of two drug combinations. The first consists of the two antihyperlipidemics: atorvastatin calcium (ATV) and ezetimibe (EZE), and the second comprises the antihypertensives: candesartan cilexetil (CAN) and hydrochlorothiazide (HCT). For mixture 1, ATV was determined using 10μg/mL EZE as the divisor to generate the ratio spectra, and the peak to trough amplitudes between 231 and 276nm were plotted against ATV concentration. Similarly, by using 10μg/mL ATV as divisor, the peak to trough amplitudes between 231 and 276nm were found proportional to EZE concentration. Calibration curves were linear in the range 2.5–40μg/mL for both drugs. For mixture 2, divisor concentration was 7.5μg/mL for both drugs. CAN was determined using its peak to trough amplitudes at 251 and 277nm, while HCT was estimated using the amplitudes between 251 and 276nm. The measured amplitudes were linearly correlated to concentration in the ranges 2.5–50 and 1–30μg/mL for CAN and HCT, respectively. The proposed spectrophotometric method was validated and successfully applied for the assay of both drug combinations in several laboratory-prepared mixtures and commercial tablets. [Copyright &y& Elsevier]