Simple, accurate, sensitive and precise UV spectrophotometric methods were developed and validated for quantitative determination of binary mixture of hydrochlorothiazide (HCZ) and amiloride hydrochloride (AM) in their bulk powder and pharmaceutical dosage forms. AM was determined in presence of HCZ by direct spectrophtometry at λmax 361 nm. Three spectrophotometric methods, namely; isoabsorptive point (I), ratio subtraction (II) and ratio difference (III) were developed for the spectral resolution of HCZ when present in mixture with AM without preliminary separation. In method (I), the isoabsorptive point (Aiso) at 277.2 nm was chosen for determination of HCZ while in method (II), HCZ was determined at λmax 270.4 nm after subtraction of interference exerted by AM. In method (III), absorption spectra of HCZ were recorded, divided by suitable divisor of AM then measuring the absorption difference at 267.6 and 290.2 nm to obtain the corresponding concentrations of HCZ. The developed methods were validated according to ICH guidelines demonstrating good accuracy and precision. The results were statistically compared with those obtained by reported ratio spectra derivative spectroscopic method indicting no significant difference and ability of methods to be used for routine analysis of proposed drugs.