Three sensitive and accurate methods are described for the direct determination of eprosartan mesylate (EPM) and hydrochlorothiazide (HCT) in bulk powder and combined dosage form without prior separation. The first method is a first derivative spectrophotometry (1D) using a zerocrossing technique of measurement at 240.7 nm for EPM and at 233.4 nm for HCT. The second method is the first derivative of ratio spectrophotometry (1DD) where the amplitudes were measured at 237.0 nm for EPM and at 277.0 nm for HCT. The third method is based on TLC separation of the two drugs followed by densitometric measurements of their spots at 290 and 270 nm for EPM and HCT, respectively. The separation was carried out on silica gel 60 F254 using n-butyl acetate-ethanol-waterammonia 33% (40:40:10:1, v/v/v/v) as mobile phase. The calibration curves were linear in the range 1.0-18.0, 2.0- 18.0 μg mL-1 and 2.0-20.0 μg/spot for EPM and 1.0-9.0, 1.0-9.0 μg mL-1 and 2.0-9.0 μg/ spot for HCT using 1D, 1DD and TLC methods, respectively. The suggested methods were tested using laboratory-prepared mixtures and were successfully applied for the analysis of pharmaceutical preparations. The methods retained their accuracy and precision when the standard addition technique was applied. The results obtained by applying the proposed methods were statistically analyzed and compared with those obtained by the manufacturer’s and USP methods for EPM and HCT, respectively.